Hydroxy, ω-carboxyaryl substituted diphenyl ureas and dirivatives thereof as raf kinase inhibitors

ABSTRACT

The invention relates to the use of a group of aryl ureas in treating raf mediated diseases and pharmaceutical compositions for use in such therapy of the formula 
     
       
         
         
             
             
         
       
         
         
           
             wherein, 
             Y is NHR 
             Hal is chlorine or bromine, 
             R is H, CH 3  or CH 2 OH, and 
             X 1  to X 7  are each, independently, H, OH or —OC(O)C 1 -C 4  alkyl, or a salt purified stereoisomer thereof, 
             wherein at least one of X 1  to X 7  is OH or —OC(O)C 1 -C 4  alkyl.

FIELD OF THE INVENTION

This invention relates to the use of a group of aryl ureas in treating raf mediated diseases, and pharmaceutical compositions for use in such therapy.

BACKGROUND OF THE INVENTION

The p21^(ras) oncogene is a major contributor to the development and progression of human solid cancers and is mutated in 30% of all human cancers (Bolton et al. Ann. Rep. Med. Chem. 1994, 29, 165-74; Bos. Cancer Res. 1989, 49, 4682-9). In its normal, unmutated form, the ras protein is a key element of the signal transduction cascade directed by growth factor receptors in almost all tissues (Avruch et al. Trends Biochem. Sci. 1994, 19, 279-83). Biochemically, ras is a guanine nucleotide binding protein, and cycling between a GTP-bound activated and a GDP-bound resting form is strictly controlled by ras' endogenous GTPase activity and other regulatory proteins. In the ras mutants in cancer cells, the endogenous GTPase activity is alleviated and, therefore, the protein delivers constitutive growth signals to downstream effectors such as the enzyme raf kinase. This leads to the cancerous growth of the cells which carry these mutants (Magnuson et al. Semin. Cancer Biol. 1994, 5, 247-53). It has been shown that inhibiting the effect of active ras by inhibiting the raf kinase signaling pathway by administration of deactivating antibodies to raf kinase or by co-expression of dominant negative raf kinase or dominant negative MEK, the substrate of raf kinase, leads to the reversion of transformed cells to the normal growth phenotype (see: Daum et al. Trends Biochem. Sci. 1994, 19, 474-80; Fridman et al. J. Biol. Chem. 1994, 269, 30105-8. Kolch et al. (Nature 1991, 349, 426-28) have further indicated that inhibition of raf expression by antisense RNA blocks cell proliferation in membrane-associated oncogenes. Similarly, inhibition of raf kinase (by antisense oligodeoxynucleotides) has been correlated in vitro and in vivo with inhibition of the growth of a variety of human tumor types (Monia et al., Nat. Med. 1996, 2, 668-75).

SUMMARY OF THE INVENTION

The present invention provides compounds which are inhibitors of the enzyme raf kinase. Since the enzyme is a downstream effector of p21^(ras), the inhibitors are useful in pharmaceutical compositions for human or veterinary use where inhibition of the raf kinase pathway is indicated, e.g., in the treatment of tumors and/or cancerous cell growth mediated by raf kinase. In particular, the compounds are useful in the treatment of human or animal solid cancers, e.g., murine cancer, since the progression of these cancers is dependent upon the ras protein signal transduction cascade and therefore susceptible to treatment by interruption of the cascade, i.e., by inhibiting raf kinase. Accordingly, the compounds of the invention are useful in treating cancers, including solid cancers, such as, for example, carcinomas (e.g., of the lungs, pancreas, thyroid, bladder or colon), myeloid disorders (e.g., myeloid leukemia) or adenomas (e.g., villous colon adenoma).

The present invention therefore provides compounds generally described as aryl ureas, including both aryl and heteroaryl analogues, which inhibit the raf kinase pathway. The invention also provides a method for treating a raf mediated disease state in humans or mammals. Thus, the invention is directed to compounds which inhibit the enzyme raf kinase and also compounds, compositions and methods for the treatment of cancerous cell growth mediated by raf kinase wherein a compound of Formula I is administered or pharmaceutically acceptable salt thereof. A-D-B  (I)

In formula I, D is —NH—C(O)—NH—,

A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L¹)_(q), where L is a 5 or 6 membered cyclic structure bound directly to D, L¹ comprises a substituted cyclic moiety having at least 5 members, M is a bridging group having at least one atom, q is an integer of from 1-3; and each cyclic structure of L and L¹ contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and

B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms with at least one 6-member cyclic structure bound directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur,

wherein L¹ is substituted by at least one substituent selected from the group consisting of —SO₂R_(x), —C(O)R_(x) and —C(NR_(y)) R_(z),

R_(y) is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo,

R_(z) is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

R_(x) is R_(z) or NR_(a)R_(b) where R_(a) and R_(b) are

a) independently hydrogen,

-   -   a carbon based moiety of up to 30 carbon atoms optionally         containing heteroatoms selected from N, S and O and optionally         substituted by halogen, hydroxy and carbon based substituents of         up to 24 carbon atoms, which optionally contain heteroatoms         selected from N, S and O and are optionally substituted by         halogen, or     -   —OSi(R_(f))₃ where R_(f) is hydrogen or a carbon based moiety of         up to 24 carbon atoms optionally containing heteroatoms selected         from N, S and O and optionally substituted by halogen, hydroxy         and carbon based substituents of up to 24 carbon atoms, which         optionally contain heteroatoms selected from N, S and O and are         optionally substituted by halogen; or

b) R_(a) and R_(b) together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or

c) one of R_(a) or R_(b) is —C(O)—, a C₁-C₅ divalent alkylene group or a substituted C₁-C₅ divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C₁-C₅ divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

where B is substituted, L is substituted or L¹ is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is up to 4;

wherein each W is independently selected from the group consisting of —CN, —CO₂R⁷, —C(O)NR⁷R⁷, —C(O)—R⁷, —NO₂, —OR⁷, —SR⁷, —NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷, —OC(O)R⁷, —Q—Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of —CN, —CO₂R⁷, —C(O)R⁷, —C(O)NR⁷R⁷, —OR⁷, —SR⁷, —NR⁷R⁷, —NO₂, —NR⁷C(O)R⁷, —NR⁷C(O)OR⁷ and halogen up to per-halo; with each R⁷ independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen,

W is preferably —OR⁷ or —OC(O)R⁷,

R⁷ is preferably H or C₁-C₄ alkyl,

wherein Q is —O—, —S—, —N(R⁷)—, —(CH₂)_(m)—, —C(O)—, —CH(OH)—, —(CH₂)_(m)O—, —(CH₂)_(m)S—, —(CH₂)_(m)N(R⁷)—, —O(CH₂)_(m)—CHX^(a)—, —CX^(a) ₂—, —S—(CH₂)_(m)— and —N(R⁷)(CH₂)_(m)—, where m=1-3, and X^(a) is halogen; and

Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Z_(n1), wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of —CN, —CO₂R⁷, —C(O)R⁷, —C(O)NR⁷R⁷, —NO₂, —OR⁷, —SR⁷ —NR⁷R⁷, —NR⁷C(O)OR⁷, —NR⁷C(O)R⁷, and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents selected from the group consisting of —CN, —CO₂R⁷, —COR⁷, —C(O)NR⁷R⁷, —OR⁷, —SR⁷, —NO₂, —NR⁷R⁷, —NR⁷C(O)R⁷, and —NR⁷C(O)OR⁷, with R⁷ as defined above.

In formula I, suitable hetaryl groups include, but are not limited to, 5-12 carbon-atom aromatic rings or ring systems containing 1-3 rings, at least one of which is aromatic, in which one or more, e.g., 1-4 carbon atoms in one or more of the rings can be replaced by oxygen, nitrogen or sulfur atoms. Each ring typically has 3-7 atoms. For example, B can be 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 1,2,3-triaz-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,3,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-,5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-6- or 7-benzisoxazolyl , 1-, 3-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 2-, 4-, 5-, 6- or 7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, or 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, or additionally optionally substituted phenyl, 2- or 3-thienyl, 1,3,4-thiadiazolyl, 3-pyrryl, 3-pyrazolyl, 2-thiazolyl or 5-thiazolyl, etc. For example, B can be 4-methyl-phenyl, 5-methyl-2-thienyl, 4-methyl-2-thienyl, 1-methyl -3-pyrryl, 1-methyl-3-pyrazolyl, 5-methyl-2-thiazolyl or 5-methyl-1,2,4-thiadiazol-2-yl.

Suitable alkyl groups and alkyl portions of groups, e.g., alkoxy, etc. throughout include methyl, ethyl, propyl, butyl, etc., including all straight-chain and branched isomers such as isopropyl, isobutyl, sec-butyl, tert-butyl, etc.

Suitable aryl groups which do not contain heteroatoms include, for example, phenyl and 1- and 2-naphthyl.

The term “cycloalkyl”, as used herein, refers to cyclic structures with or without alkyl substituents such that, for example, “C₄ cycloalkyl” includes methyl substituted cyclopropyl groups as well as cyclobutyl groups. The term “cycloalkyl”, as used herein also includes saturated heterocyclic groups.

Suitable halogen groups include F, Cl, Br, and/or I, from one to per-substitution (i.e. all H atoms on a group replaced by a halogen atom) being possible where an alkyl group is substituted by halogen, mixed substitution of halogen atom types also being possible on a given moiety.

Preference is given to a compound of formula (Ia)

-   -   wherein,     -   Y is NHR,     -   Hal is chlorine or bromine,     -   R is H, CH₃ or CH₂OH, and     -   X¹ to X⁷ are each, independently, H, OH or —OC(O)C₁-C₄ alkyl,     -   or a salt or purified stereoisomer thereof,     -   with the proviso that at least one of X¹ to X⁷ is OH or         —OC(O)C₁-C₄ alkyl.

Further preferance is given to a compound of formula (Ib),

-   -   wherein,     -   Y is NHR,     -   Hal is chlorine or bromine,     -   R is H, CH₃ or CH₂OH, and     -   X⁴ to X⁷ are each, independently, H, OH or —OC(O)C₁-C₄ alkyl,     -   or a salt or purified stereoisomer thereof,     -   with the proviso that at least one of X⁴ to X⁷ is OH or         —OC(O)C₁-C₄ alkyl.

Further preferance is given to a compound of formula (Ic),

-   -   wherein,     -   Hal is chlorine or bromine, and     -   X¹ to X⁷ are each, independently, H, OH or —OC(O)C₁-C₄ alkyl,     -   or a salt or purified stereoisomer thereof.

Preferred compounds of this invention include 4-{4-[({[4-chloro-3-(trifluoromethyl) phenyl]amino}carbonyl)amino]2-(hydroxy)phenoxy}-2-pyridine carboxamide, 4-{4-[({[4-chloro-3-(trifluoromethyl) phenyl]amino}carbonyl)amino]3-(hydroxy)phenoxy}-2-pyridine carboxamide, 4-{4-[({[4-chloro-3-(trifluoromethyl) phenyl]amino}carbonyl)amino]5-(hydroxy)phenoxy}-2-pyridine carboxamide, and 4-{4-[({[4-chloro-3-(trifluoromethyl) phenyl]amino}carbonyl)amino]6-(hydroxy)phenoxy}-2-pyridine carboxamide.

The present invention is also directed to pharmaceutically acceptable salts of formulae (I), (Ia), (Ib) and (Ic). Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1-napbthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. In addition, pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (e.g., Li⁺ Na⁺ or K⁺), alkaline earth cations (e.g., Mg⁺², Ca⁺² or Ba⁺²), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations, such as those arising from protonation or peralkylation of triethylamine, N,N-diethylamine, N,N-dicyclohexylamine, lysine, pyridine, N,N-dimethylaminopyridine (DMAP), 1,4-diazabiclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

A number of the compounds of formulae (I), (Ia), (Ib) and (Ic) possess asymmetric carbons and can therefor exist in racemic and optically active forms. Methods of separation of enantiomeric and diastereomeric mixtures are well known to one skilled in the art. The present invention encompasses any isolated racemic or optically active form of compounds described in Formula I which possess raf inhibitory activity.

One of ordinary skill in the art will recognize that some of the compounds of formulae (I), (Ia), (Ib) and (Ic) can exist in different geometrical isomeric forms. In addition, some of the compounds of the present invention possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers, as well as in the form of racemic or nonracemic mixtures thereof, and in the form of diastereomers and diastereomeric mixtures. All of these compounds, including cis isomers, trans isomers, diastereomic mixtures, racemates, nonracemic mixtures of enantiomers, substantially pure, and pure enantiomers, are considered to be within the scope of the present invention. Herein, substantially pure enantiomers is intended to mean that no more than 5% w/w of the corresponding opposite enantiomer is present.

The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. The optically active bases or acids are liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of a chiral chromatography column (e.g., chiral HPLC columns) optimally chosen to maximize the separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ. The optically active compounds of Formula (I) can likewise be obtained by utilizing optically active starting materials.

The compounds of formulae (I), (Ia), (Ib) and (Ic), including all steroisomeric forms thereof (both isolated and in mixtures), the salts thereof and analogs thereof are collectively referred to herein as “the compounds ogf this invention.”

The invention also relates to a method of treating or preventing cancer and other hyperproliferative disorders by administering a compound of the invention, or a pharmaceutical composition comprising one or more compounds of the invention, in combination with a cytotoxic agent.

Optional anti-proliferative agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11^(th) Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, and vindesine.

Other anti-proliferative agents suitable for use with the composition of the invention include but are not limited to those compounds acknowldeged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated by reference such as aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol, 2′, 2′-difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, gemcitabine, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, and vinorelbine.

Other anti-proliferative agents suitable for use with the composition of the invention include but are not limited to other anti-cancer agents such as epothilone, irinotecan, raloxifen and topotecan.

Cancer and hyperproliferative disorders are defined as follows. These disorders include but are not limited to solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukemias.

Examples of breast cancer include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are not limited to small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.

Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer.

Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.

Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallblader, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.

Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, and urethral cancers.

Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

Head-and-neck cancers include, but are not limited to laryngeal/hypopharyngeal/nasopharyngeal/oropharyngeal cancer, and lip and oral cavity cancer. Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma. Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

These disorders have been well characterized in man, but also exist with a similar etiology in other mammals, and can be treated by pharmaceutical compositions of the present invention.

Generally, the use of cytotoxic and/or cytostatic agents in combination with aryl urea compound raf kinase inhibitors will serve to (1) yield better efficacy in reducing the growth of a tumor or even eliminate the tumor as compared to administration of either agent alone, (2) provide for the administration of lesser amounts of the administered chemotherapeutic agents, (3) provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies, (4) provide for treating a broader spectrum of different cancer types in mammals, especially humans, (5) provide for a higher response rate among treated patients, (6) provide for a longer survival time among treated patients compared to standard chemotherapy treatments, (7) provide a longer time for tumor progression, and/or (8) yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.

The present invention relates to a combination comprising (a) a compound according to the invention (b) at least one other chemotherapeutic cytotoxic or cytostatic agent; or pharmaceutically acceptable salts of any component (a) or (b).

The invention also relates to a pharmaceutical preparation which comprises (1) quantities of (a) a compound according to the invention (b) at least one other cytotoxic or cytostatic agent in amounts which are jointly effective for treating a cancer, where any component (a) or (b) can also be present in the form of a pharmaceutically acceptable salt if at least one salt-forming group is present, with (2) one or more pharmaceutically acceptable carrier molecules.

The invention also relates to a method for treating a cancer that can be treated by administration of a compound according to the invention and at least one other chemotherapeutic agent which is a cytotoxic or cytostatic agent. The compound according to the invention and the cytotoxic or cytostatic agent are administered to a mammal in quantities which together are therapeutically effective against proliferative diseases, including but not limited to colon, gastric, lung, pancreatic, ovarian, prostate, leukemia, melanoma, hepatocellular, renal, head and neck, glioma, and mammary cancers. Thus, the compound according to the invention is effective for raf kinase-mediated cancers. However, these compounds are also effective for cancers not mediated by raf kinase.

Suitable cytotoxic or cytostatic agents used in the present invention include but are not limited to irinotecan, vinorelbine, gemcitabine, paclitaxel, taxotere, doxorubicin, cisplatin, carboplatin, BCNU, CCNU, DTIC, melphalan, cyclophosphamide, ara A, ara C, etoposide, vincristine, vinblastine, actinomycin D, 5-fluorouracil, methotrexate, herceptin, and mitomycin C.

The present invention provides methods for treating a cancer in a mammal, especially a human patient, comprising administering an a compound according to the invention in combination with a cytotoxic or cytostatic chemotherapeutic agent including but not limited to DNA topoisomerase I and II inhibitors, DNA intercalators, alkylating agents, microtubule disruptors, hormone and growth factor receptor agonists or antagonists, other kinase inhibitors and antimetabolites.

In another embodiment, the methods of the present invention can be used to treat a variety of human cancers, including but not limited to pancreatic, lung, colon, ovarian, prostate, leukemia, melanoma, hepatocellular, renal, head and neck, glioma, and mammary carcinomas.

In another embodiment, a method is disclosed for administering the chemotherapeutic agents, including a compound according to the invention and the cytotoxic and cytostatic agents, to the patient by oral delivery or by intravenous injection or infusion.

In another embodiment, the composition comprising a compound according to the invention or the cytotoxic or cytostatic agent can be administered to a patient in the form of a tablet, a liquid, a topical gel, an inhaler or in the form of a sustained release composition.

In one embodiment of the invention, a compound according to the invention can be administered simultaneously with a cytotoxic or cytostatic agent to a patient with a cancer, in the same formulation or, more typically in separate formulations and, often, using different administration routes. Administration can also be sequentially, in any order.

In another embodiment, a compound according to the invention can be administered in tandem with the cytotoxic or cytostatic agent, wherein a compound according to the invention can be administered to a patient once or more per day for up to 28 consecutive days with the concurrent or intermittent administration of a cytotoxic or cytostatic agent over the same total time period.

In another embodiment of the invention, a compound according to the invention can beadministered to a patient at an oral, intravenous, intramuscular, subcutaneous, or parenteral dosage which can range from about 0.1 to about 300 mg/kg of total body weight.

In another embodiment, the cytotoxic or cytostatic agent can be administered to a patient at an intravenous, intramuscular, subcutaneous, or parenteral dosage which can range from about 0.1 mg to 300 mg/kg of patient body weight.

Further, the invention relates to a method of inhibiting proliferation of cancer cells comprising contacting cancer cells with a pharmaceutical preparation or product of the invention, especially a method of treating a proliferative disease comprising contacting a subject, cells, tissues or a body fluid of said subject, suspected of having a cancer with a pharmaceutical composition or product of this invention.

This invention also relates to compositions containing both a compound according to the invention and the other cytotoxic or cytostatic agents, in the amounts of this invention.

This invention further relates to kits comprising separate doses of the two mentioned chemotherapeutic agents in separate containers. The combinations of the invention can also be formed in vivo, e.g., in a patient's body.

The term “cytotoxic” refers to an agent which can be administered to kill or eliminate a cancer cell. The term “cytostatic” refers to an agent which can be administered to restrain tumor proliferation rather than induce cytotoxic cytoreduction yielding an elimination of the cancer cell from the total viable cell population of the patient. The chemotherapeutic agents described herein, e.g., irinotecan, vinorelbine, gemcitabine, and paclitaxel are considered cytotoxic agents. These cytotoxic and cytostatic agents have gained wide spread use as chemotherapeutics in the treatment of various cancer types and are well known.

These and other cytotoxic/cytostatic agents can be administered in the conventional formulations and regimens in which they are known for use alone.

General Preparative Methods

The compounds of Formula I may be prepared by the use of known chemical reactions and procedures, some from starting materials which are commercially available. Nevertheless, general preparative methods are provided below to aid one skilled in the art in synthesizing these compounds, with more detailed examples being provided in the Experimental section which follows.

Substituted anilines may be generated using standard methods (March. Advanced Organic Chemistry, 3^(rd) Ed.; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)). As shown in Scheme I, aryl amines are commonly synthesized by reduction of nitroaryls using a metal catalyst, such as Ni, Pd, or Pt, and H₂ or a hydride transfer agent, such as formate, cyclohexadiene, or a borohydride (Rylander. Hydrogenation Methods; Academic Press: London, UK (1985)). Nitroaryls may also be directly reduced using a strong hydride source, such as LiAlH₄ (Seyden-Penne. Reductions by the Alumino- and Borohydrides in Organic Synthesis; VCH Publishers: New York (1991)), or using a zero valent metal, such as Fe, Sn or Ca, often in acidic media. Many methods exist for the synthesis of nitroaryls (March. Advanced Organic Chemistry, 3^(rd) Ed.; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)).

Nitroaryls are commonly formed by electrophilic aromatic nitration using HNO₃, or an alternative NO₂ ⁺ source. Nitroaryls may be further elaborated prior to reduction. Thus, nitroaryls substituted with

potential leaving groups (e.g. F, Cl, Br, etc.) may undergo substitution reactions on treatment with nucleophiles, such as thiolate (exemplified in Scheme II) or phenoxide. Nitroaryls may also undergo Ullman-type coupling reactions (Scheme II).

Nitroaryls may also undergo transition metal mediated cross coupling reactions. For example, nitroaryl electrophiles, such as nitroaryl bromides, iodides or triflates, undergo palladium mediated cross coupling reactions with aryl nucleophiles, such as arylboronic acids (Suzuki reactions, exemplified below), aryltins (Stille reactions) or arylzincs (Negishi reaction) to afford the biaryl (5).

Either nitroaryls or anilines may be converted into the corresponding arenesulfonyl chloride (7) on treatment with chlorosulfonic acid. Reaction of the sulfonyl chloride with a fluoride source, such as KF then affords sulfonyl fluoride (8). Reaction of sulfonyl fluoride 8 with trimethylsilyl trifluoromethane in the presence of a fluoride source, such as tris(dimethylamino)sulfonium difluorotrimethylsiliconate (TASF) leads to the corresponding trifluoromethylsulfone (9). Alternatively, sulfonyl chloride 7 may be reduced to the arenethiol (10), for example with zinc amalgum. Reaction of thiol 10 with CHCIF₂ in the presence of base gives the difluoromethyl mercaptam (11), which may be oxidized to the sulfone (12) with any of a variety of oxidants, including CrO₃-acetic anhydride (Sedova et al. Zh. Org. Khim. 1970, 6, (568).

As shown in Scheme IV, non-symmetrical urea formation may involve reaction of an aryl isocyanate (14) with an aryl amine (13). The heteroaryl isocyanate may be synthesized from a heteroaryl amine by treatment with phosgene or a phosgene equivalent, such as trichloromethyl chloroformate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), or N,N′-carbonyldiimidazole (CDI). The isocyanate may also be derived from a heterocyclic carboxylic acid derivative, such as an ester, an acid halide or an anhydride by a Curtius-type rearrangement. Thus, reaction of acid derivative 16 with an azide source, followed by rearrangement affords the isocyanate. The corresponding carboxylic acid (17) may also be subjected to Curtius-type rearrangements using diphenylphosphoryl azide (DPPA) or a similar reagent.

Finally, ureas may be further manipulated using methods familiar to those skilled in the art.

The invention also includes pharmaceutical compositions including a compound of Formula I, and a physiologically acceptable carrier.

The compounds may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations. The term ‘administration by injection’ includes intravenous, intramuscular, subcutaneous and parenteral injections, as well as use of infusion techniques. One or more compounds may be present in association with one or more non-toxic pharmaceutically acceptable carriers and if desired other active ingredients.

Compositions intended for oral use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. These compounds may also be prepared in solid, rapidly released form.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example, lecithin, or condensation products or an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.

The compounds may also be in the form of non-aqueous liquid formulations, e.g., oily suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.

The compounds may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.

For all regimens of use disclosed herein for compounds of Formula I, the daily oral dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily rectal dosage regime will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily topical dosage regime will preferably be from 0.1 to 200 mg administered between one to four times daily. The daily inhalation dosage regime will preferably be from 0.01 to 10 mg/Kg of total body weight.

It will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be appreciated by one skilled in the art that the specific dose level for a given patient depends on a variety of factors, including specific activity of the compound administered, age, body weight, health, sex, diet, time and route of administration, rate of excretion, etc. It will be further appreciated by one skilled in the art that the optimal course of treatment, ie., the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the condition undergoing therapy.

The entire enclosure of all applications, patents and publications cited above and below are hereby incorporated by reference. Including provisional application Ser. No. 60/115,877, filed Jan. 13, 1999 and non-provisional application Ser. No. 09/257,266 filed Feb. 25, 1999.

The compounds can be produced from known compounds (or from starting materials which, in turn, can be produced from known compounds), e.g., through the general preparative methods shown below. The activity of a given compound to inhibit raf kinase can be routinely assayed, e.g., according to procedures disclosed below. The following examples are for illustrative purposes only and are not intended, nor should they be construed to limit the invention in any way.

EXAMPLES

All reactions were performed in flame-dried or oven-dried glassware under a positive pressure of dry argon or dry nitrogen, and were stirred magnetically unless otherwise indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Unless otherwise stated, the term ‘concentration under reduced pressure’ refers to use of a Buchi rotary evaporator at approximately 15 mmHg (0.0197 atm). Unless otherwise stated, the term ‘under high vacuum’ refers to a vacuum of 0.4-1.0 mmHg (5.2-13.2×10⁻⁴ atm).

All temperatures are reported uncorrected in degrees Celsius (° C.). Unless otherwise indicated, all parts and percentages are by weight.

Commercial grade reagents and solvents were used without further purification. N-cyclohexyl-N′-(methylpolystyrene)carbodiimide was purchased from Calbiochem-Novabiochem Corp. 3-tert-Butylaniline, 5-tert-butyl-2-methoxyaniline, 4-bromo-3-(trifluoromethyl)aniline, 4-chloro-3-(trifluoromethyl)aniline 2-methoxy-5-(trifluoromethyl)aniline, 4-tert-butyl-2-nitroaniline, 3-amino-2-naphthol, ethyl 4-isocyanatobenzoate, N-acetyl-4-chloro-2-methoxy-5-(trifluoromethyl)aniline and 4-chloro-3-(trifluoromethyl)phenyl isocyanate were purchased and used without further purification. Syntheses of 3-amino-2-methoxyquinoline (E. Cho et al. WO 98/00402; A. Cordi et al. EP 542,609; IBID Bioorg. Med. Chem. 3, 1995, 129), 4-(3-carbamoylphenoxy)-1-nitrobenzene (K. Ikawa Yakugaku Zasshi 79, 1959, 760; Chem. Abstr. 53, 1959, 12761b), 3-tert-butylphenyl isocyanate (O. Rohr et al. DE 2,436,108) and 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (K. Inukai et al. JP 42,025,067; IBID Kogyo Kagaku Zasshi 70, 1967, 491) have previously been described.

Thin-layer chromatography (TLC) was performed using Whatman® pre-coated glass-backed silica gel 60A F-254 250 μm plates. Visualization of plates was effected by one or more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, (d) immersion of the plate in a cerium sulfate solution followed by heating, and/or (e) immersion of the plate in an acidic ethanol solution of 2,4-dinitrophenylhydrazine followed by heating. Column chromatography (flash chromatography) was performed using 230-400 mesh EM Science® silica gel.

Melting points (mp) were determined using a Thomas-Hoover melting point apparatus or a Mettler FP66 automated melting point apparatus and are uncorrected. Fourier transform infrared spectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer. Proton (¹H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me₄Si (δ 0.00) or residual protonated solvent (CHCl₃δ 7.26; MeOH δ 3.30; DMSO δ 2.49) as standard. Carbon (¹³C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDCl₃δ 77.0; MeOD-d₃; δ 49.0; DMSO-d₆ δ 39.5) as standard. Low resolution mass spectra (MS) and high resolution mass spectra (HRMS) were either obtained as electron impact (EI) mass spectra or as fast atom bombardment (FAB) mass spectra. Electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Vacumetrics Desorption Chemical Ionization Probe for sample introduction. The ion source was maintained at 250° C. Electron impact ionization was performed with electron energy of 70 eV and a trap current of 300 μA. Liquid-cesium secondary ion mass spectra (FAB-MS), an updated version of fast atom bombardment were obtained using a Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained using a Hewlett Packard MS-Engine (5989A) with methane or ammonia as the reagent gas (1×10⁻⁴ torr to 2.5×10⁻⁴ torr). The direct insertion desorption chemical ionization (DCI) probe (Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held at 10 amps until all traces of the sample disappeared (˜1-2 min). Spectra were scanned from 50-800 amu at 2 sec per scan. HPLC—electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a C-18 column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-800 amu using a variable ion time according to the number of ions in the source. Gas chromatography—ion selective mass spectra (GC-MS) were obtained with a Hewlett Packard 5890 gas chromatograph equipped with an HP-1 methyl silicone column (0.33 mM coating; 25 m×0.2 mm) and a Hewlett Packard 5971 Mass Selective Detector (ionization energy 70 eV). Elemental analyses are conducted by Robertson Microlit Labs, Madison N.J.

All compounds displayed NMR spectra, LRMS and either elemental analysis or HRMS consistent with assigned structures.

List of Abbreviations and Acronyms: AcOH acetic acid anh anhydrous atm atmosphere(s) BOC tert-butoxycarbonyl CDI 1,1′-carbonyl diimidazole conc concentrated d day(s) dec decomposition DMAC N,N-dimethylacetamide DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone DMF N,N-dimethylformamide DMSO dimethylsulfoxide DPPA diphenylphosphoryl azide EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide EtOAc ethyl acetate EtOH ethanol (100%) Et₂O diethyl ether Et₃N triethylamine h hour(s) HOBT 1-hydroxybenzotriazole m-CPBA 3-chloroperoxybenzoic acid MeOH methanol pet. ether petroleum ether (boiling range 30-60° C.) temp. temperature THF tetrahydrofuran TFA trifluoroAcOH Tf trifluoromethanesulfonyl

-   A. General Methods for Synthesis of Substituted Anilines -   A1. General Method for Aryl Amine Formation via Ether Formation     Followed by Ester Saponification, Curtius Rearrangement, and     Carbamate Deprotection. Synthesis of 2-Amino-3-methoxynaphthalene.

Step 1. Methyl 3-methoxy-2-naphthoate

A slurry of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 mmol) and K₂CO₃ (7.96 g, 57.6 mmol) in DMF (200 mL) was stirred at room temp. for 15 min., then treated with iodomethane (3.43 mL, 55.1 mmol). The mixture was allowed to stir at room temp. overnight, then was treated with water (200 mL). The resulting mixture was extracted with EtOAc (2×200 mL). The combined organic layers were washed with a saturated NaCl solution (100 mL), dried (MgSO₄), concentrated under reduced pressure (approximately 0.4 mmHg (5.2×10⁻⁴ atm) overnight) to give methyl 3-methoxy-2-naphthoate as an amber oil (10.30 g): ¹H-NMR (DMSO-d₆) δ 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app t, J=8.09 Hz, 1H), 7.44 (s, 1H), 7.53 (app t, J=8.09 Hz, 1H), 7.84 (d, J=8.09 Hz, 1H), 7.90 (s, 1H), 8.21 (s, 1H).

Step 2. 3-Methoxy-2-naphthoic acid

A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10 mL) in MeOH (100 mL) at room temp. was treated with a 1 N NaOH solution (33.4 mL, 33.4 mmol). The mixture was heated at the reflux temp. for 3 h, cooled to room temp., and made acidic with a 10% citric acid solution. The resulting solution was extracted with EtOAc (2×100 mL). The combined organic layers were washed with a saturated NaCl solution, dried (MgSO₄) and concentrated under reduced pressure. The residue was triturated with hexane then washed several times with hexane to give 3-methoxy-2-naphthoic acid as a white solid (5.40 g, 92%): ¹H-NMR (DMSO-d₆) δ 3.88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54 (m, 1H), 7.83 (d, J=8.09 Hz, 1H), 7.91 (d, J=8.09 Hz, 1H), 8.19 (s, 1H), 12.83 (brs, 1H).

Step 3. 2-(N-(Carbobenzyloxy)amino-3-methoxynaphthalene

A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) and Et₃N (2.59 mL, 18.6 mmol) in anh toluene (70 mL) was stirred at room temp. for 15 min., then treated with a solution of DPPA (5.12 g, 18.6 mmol) in toluene (10 mL) via pipette. The resulting mixture was heated at 80° C. for 2 h. After cooling the mixture to room temp., benzyl alcohol (2.06 mL, 20 mmol) was added via syringe. The mixture was then warmed to 80° C. overnight. The resulting mixture was cooled to room temp., quenched with a 10% citric acid solution, and extracted with EtOAc (2×100 mL). The combined organic layers were washed with a saturated NaCl solution, dried (MgSO₄) and concentrated under reduced pressure. The residue was purified by column chromatography (14% EtOAc/86% hexane) to give 2-(N-(carbobenzyloxy)amino-3-methoxynaphthalene as a pale yellow oil (5.1 g, 100%): ¹H-NMR (DMSO-d₆) δ 3.89 (s, 3H), 5.17 (s, 2H), 7.27-7.44 (m, 8H), 7.72-7.75 (m, 2H), 8.20 (s, 1H), 8.76 (s, 1H).

Step 4. 2-Amino-3-methoxynaphthalene

A slurry of 2-(N-(carbobenzyloxy)amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and 10% Pd/C (0.5 g) in EtOAc (70 mL) was maintained under a H₂ atm (balloon) at room temp. overnight. The resulting mixture was filtered through Celite® and concentrated under reduced pressure to give 2-amino-3-methoxynaphthalene as a pale pink powder (2.40 g, 85%): ¹H-NMR (DMSO-d₆) δ 3.86 (s, 3H), 6.86 (s, 2H), 7.04-7.16 (m, 2H), 7.43 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H); EI-MS m/z 173 (M⁺).

-   A2. Synthesis of ω-Carbamyl Anilines via Formation of a     Carbamylpyridine Followed by Nucleophilic Coupling with an Aryl     Amine. Synthesis of 4-(2-N-Methylcarbamyl-4-pyridyloxy)aniline

Step 1a. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide via the Menisci Reaction

Caution: this is a highly hazardous, potentially explosive reaction. To a stirring solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL) at room temp. was added conc. H₂SO₄ (3.55 mL) to generate an exotherm. To this mixture was added H₂O₂ (30% wt in H₂O, 17 mL) followed by FeSO₄.7H₂O (0.56 g) to generate another exotherm. The resulting mixture was stirred in the dark at room temp. for 1 h, then warmed slowly over 4 h to 45° C. When bubbling had subsided, the reaction was heated at 60° C. for 16 h. The resulting opaque brown solution was diluted with H₂O (700 mL) followed by a 10% NaOH solution (250 mL). The resulting mixture was extracted with EtOAc (3×500 mL). The organic phases were washed separately with a saturated NaCl solution (3×150 mL), then they were combined, dried (MgSO₄) and filtered through a pad of silica gel with the aid of EtOAc. The resulting brown oil was purified by column chromatography (gradient from 50% EtOAc/50% hexane to 80% EtOAc/20% hexane). The resulting yellow oil crystallized at 0° C. over 72 h to give 4-chloro-N-methyl-2-pyridinecarboxamide (0.61 g, 5.3%): TLC (50% EtOAc/50% hexane) R_(f)0.50; ¹H NMR (CDCl₃) δ 3.04 (d, J=5.1 Hz, 3H), 7.43 (dd, J=5.4, 2.4 Hz, 1H), 7.96 (brs, 1H), 8.21 (s, 1H), 8.44 (d, J=5.1 Hz, 1 H); CI-MS m/z 171 ((M+H)⁺).

Step 1b. Synthesis of 4-chloropyridine-2-carbonyl chloride HCl salt via picolinic acid

Anhydrous DMF (6.0 mL) was slowly added to SOCl₂ (180 mL) between 40° and 50° C. The solution was stirred in that temperature range for 10 min. then picolinic acid (60.0 g, 487 mmol) was added in portions over 30 min. The resulting solution was heated at 72° C. (vigorous SO₂ evolution) for 16 h to generate a yellow solid precipitate. The resulting mixture was cooled to room temp., diluted with toluene (500 mL) and concentrated to 200 mL. The toluene addition/concentration process was repeated twice. The resulting nearly dry residue was filtered and the solids were washed with toluene (2×200 mL) and dried under high vacuum for 4 h to afford 4-chloropyridine-2-carbonyl chloride HCl salt as a yellow-orange solid (92.0 g, 89%).

Step 2. Synthesis of methyl 4-chloropyridine-2-carboxylate HCl salt

Anh DMF (10.0 mL) was slowly added to SOCl₂ (300 mL) at 40-48° C. The solution was stirred at that temp. range for 10 min., then picolinic acid (100 g, 812 mmol) was added over 30 min. The resulting solution was heated at 72° C. (vigorous SO₂ evolution) for 16 h to generate a yellow solid. The resulting mixture was cooled to room temp., diluted with toluene (500 mL) and concentrated to 200 mL. The toluene addition/concentration process was repeated twice. The resulting nearly dry residue was filtered, and the solids were washed with toluene (50 mL) and dried under high vacuum for 4 hours to afford 4-chloropyridine-2-carbonyl chloride HCl salt as an off-white solid (27.2 g, 16%). This material was set aside.

The red filtrate was added to MeOH (200 mL) at a rate which kept the internal temperature below 55° C. The contents were stirred at room temp. for 45 min., cooled to 5° C. and treated with Et₂O (200 mL) dropwise. The resulting solids were filtered, washed with Et₂O (200 mL) and dried under reduced pressure at 35° C. to provide methyl 4-chloropyridine-2-carboxylate HCl salt as a white solid (110 g, 65%): mp 108-112° C.; ¹H-NMR (DMSO-d₆) δ3.88 (s, 3H); 7.82 (dd, J=5.5, 2.2 Hz, 1H); 8.08 (d, J=2.2 Hz, 1H); 8.68 (d, J=5.5 Hz, 1H); 10.68 (brs, 1H); HPLC ES-MS m/z 172 ((M+H)⁺).

Step 3a. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from methyl 4-chloropyridine-2-carboxylate

A suspension of methyl 4-chloropyridine-2-carboxylate HCl salt (89.0 g, 428 mmol) in MeOH (75 mL) at 0°0 C. was treated with a 2.0 M methylamine solution in THF (1 L) at a rate which kept the internal temp. below 5° C. The resulting mixture was stored at 3° C. for 5 h, then concentrated under reduced pressure. The resulting solids were suspended in EtOAc (1 L) and filtered. The filtrate was washed with a saturated NaCl solution (500 mL), dried (Na₂SO₄) and concentrated under reduced pressure to afford 4-chloro-N-methyl-2-pyridinecarboxamide as pale-yellow crystals (71.2 g, 97%): mp 41-43° C.; ¹H-NMR (DMSO-d₆) δ 2.81 (s, 3H), 7.74 (dd, J=5.1, 2.2 Hz, 1H), 8.00 (d, J=2.2, 1H), 8.61 (d, J=5.1 Hz, 1H), 8.85 (brd, 1H); CI-MS m/z 171 ((M+H)⁺).

Step 3b. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from 4-chloropyridine-2-carbonyl chloride

4-Chloropyridine-2-carbonyl chloride HCl salt (7.0 g, 32.95 mmol) was added in portions to a mixture of a 2.0 M methylamine solution in THF (100 mL) and MeOH (20 mL) at 0° C. The resulting mixture was stored at 3° C. for 4 h, then concentrated under reduced pressure. The resulting nearly dry solids were suspended in EtOAc (100 mL) and filtered. The filtrate was washed with a saturated NaCl solution (2×100 mL), dried (Na₂SO₄) and concentrated under reduced pressure to provide 4-chloro-N-methyl-2-pyridinecarboxamide as a yellow, crystalline solid (4.95 g, 88%): mp 37-40° C.

Step 4. Synthesis of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline

A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anh. DMF (150 mL) was treated with potassium tert-butoxide (10.29 g, 91.7 mmol), and the reddish-brown mixture was stirred at room temp. for 2 h. The contents were treated with 4-chloro-N-methyl-2-pyridinecarboxamide (15.0 g, 87.9 mmol) and K₂CO₃ (6.50 g, 47.0 mmol) and then heated at 80° C. for 8 h. The mixture was cooled to room temp. and separated between EtOAc (500 mL) and a saturated NaCl solution (500 mL). The aqueous phase was back-extracted with EtOAc (300 mL). The combined organic layers were washed with a saturated NaCl solution (4×1000 mL), dried (Na₂SO₄) and concentrated under reduced pressure. The resulting solids were dried under reduced pressure at 35° C. for 3 h to afford 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline as a light-brown solid 17.9 g, 84%): ¹H-NMR (DMSO-d₆) δ 2.77 (d, J=4.8 Hz, 3H), 5.17 (brs, 2H), 6.64, 6.86 (AA′BB′ quartet, J=8.4 Hz, 4H), 7.06 (dd, J=5.5, 2.5 Hz, 1H), 7.33 (d, J=2.5 Hz, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.73 (brd, 1H); HPLC ES-MS m/z 244 ((M+H)⁺).

-   A3. General Method for the Synthesis of Anilines by Nucleophilic     Aromatic Addition Followed by Nitroarene Reduction. Synthesis of     5-(4-Aminophenoxy)isoindoline-1,3-dione

Step 1. Synthesis of 5-hydroxyisoindoline-1,3-dione

To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in conc. AcOH (25 mL) was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated at 120° C. for 45 min., then the clear, bright yellow mixture was heated at 160° C. for 2 h. The resulting mixture was maintained at 160° C. and was concentrated to approximately 15 mL, then was cooled to room temp. and adjusted pH 10 with a 1N NaOH solution. This mixture was cooled to 0° C. and slowly acidified to pH 5 using a 1N HCl solution. The resultant precipitate was collected by filtration and dried under reduced pressure to yield 5-hydroxyisoindoline-1,3-dione as a pale yellow powder as product (3.24 g, 72%): ¹H NMR (DMSO-d₆) δ 7.00-7.03 (m, 2H), 7.56 (d, J=9.3 Hz, 1H).

Step 2. Synthesis of 5-(4-nitrophenoxy)isoindoline-1,3-dione

To a stirring slurry of NaH (1.1 g, 44.9 mmol) in DMF (40 mL) at 0° C. was added a solution of 5-hydroxyisoindoline-1,3-dione (3.2 g, 19.6 mmol) in DMF (40 mL) dropwise. The bright yellow-green mixture was allowed to return to room temp. and was stirred for 1 h, then 1-fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added via syringe in 3-4 portions. The resulting mixture was heated at 70° C. overnight, then cooled to room temp. and diluted slowly with water (150 mL), and extracted with EtOAc (2×100 mL). The combined organic layers were dried (MgSO₄) and concentrated under reduced pressure to give 5-(4-nitrophenoxy)isoindoline-1,3-dione as a yellow solid (3.3 g, 62%): TLC (30% EtOAc/70% hexane) R_(f)0.28; 1H NMR (DMSO-d₆) δ 7.32 (d, J=12 Hz, 2H), 7.52-7.57 (m, 2H), 7.89(d, J=7.8 Hz, 1H), 8.29 (d, J=9 Hz, 2H), 11.43 (brs, 1H); CI-MS m/z 285 ((M+H)⁺, 100%).

Step 3. Synthesis of 5-(4-aminophenoxy)isoindoline-1,3-dione

A solution of 5-(4-nitrophenoxy)isoindoline-1,3-dione (0.6 g, 2.11 mmol) in conc. AcOH (12 mL) and water (0.1 mL) was stirred under stream of argon while iron powder (0.59 g, 55.9 mmol) was added slowly. This mixture stirred at room temp. for 72 h, then was diluted with water (25 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried (MgSO₄) and concentrated under reduced pressure to give 5-(4-aminophenoxy)isoindoline-1,3-dione as a brownish solid (0.4 g, 75%): TLC (50% EtOAc/50% hexane) R_(f)0.27; ¹H NMR (DMSO-d₆) δ 5.14 (brs, 2H), 6.62 (d, J=8.7 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 7.03 (d, J=2.1 Hz, 1H), 7.23 (dd, 1H), 7.75 (d, J=8.4 Hz, 1H), 11.02 (s, 1H); HPLC ES-MS m/z 255 ((M+H)⁺, 100%).

-   A4. General Method for the Synthesis of Pyrrolylanilines. Synthesis     of 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline

Step 1. Synthesis of 1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole

To a stirring solution of 2-nitro-4-tert-butylaniline (0.5 g, 2.57 mmol) in cyclohexane (10 mL) was added AcOH (0.1 mL) and acetonylacetone (0.299 g, 2.63 mmol) via syringe. The reaction mixture was heated at 120° C. for 72 h with azeotropic removal of volatiles. The reaction mixture was cooled to room temp., diluted with CH₂Cl₂ (10 mL) and sequentially washed with a 1N HCl solution (15 mL), a 1N NaOH solution (15 mL) and a saturated NaCl solution (15 mL), dried (MgSO₄) and concentrated under reduced pressure. The resulting orange-brown solids were purified via column chromatography (60 g SiO₂; gradient from 6% EtOAc/94% hexane to 25% EtOAc/75% hexane) to give 1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole as an orange-yellow solid (0.34 g, 49%): TLC (15% EtOAc/85% hexane) R_(f) 0.67; ¹H NMR (CDCl₃) d 1.34 (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H), 7.19-7.24 (m, 1H), 7.62 (dd, 1H), 7.88 (d, J=2.4 Hz, 1H); CI-MS m/z 273 ((M+H)⁺, 50%).

Step 2. Synthesis of 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline

A slurry of 1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole (0.341 g, 1.25 mmol), 10% Pd/C (0.056 g) and EtOAc (50 mL) under an H₂ atmosphere (balloon) was stirred for 72 h, then filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to give 5-tert-butyl-2-(2,5-dimethylpyrrolyl)aniline as yellowish solids (0.30 g, 99%): TLC (10% EtOAc/90% hexane) R_(f)0.43; ¹H NMR (CDCl₃) δ 1.28 (s, 9H), 1.87-1.91 (m, 8H), 5.85 (brs, 2H), 6.73-6.96 (m, 3H), 7.28 (brs, 1H).

-   A5. General Method for the Synthesis of Anilines from Anilines by     Nucleophilic Aromatic Substitution. Synthesis of     4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline HCl Salt

A solution of 4-amino-3-methylphenol (5.45 g, 44.25 mmol) in dry dimethylacetamide (75 mL) was treated with potassium tert-butoxide (10.86 g, 96.77 mmol) and the black mixture was stirred at room temp. until the flask had reached room temp. The contents were then treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step 3b; 7.52 g, 44.2 mmol) and heated at 110° C. for 8 h. The mixture was cooled to room temp. and diluted with water (75 mL). The organic layer was extracted with EtOAc (5×100 mL). The combined organic layers were washed with a saturated NaCl solution (200 mL), dried (MgSO₄) and concentrated under reduced pressure. The residual black oil was treated with Et₂O (50 mL) and sonicated. The solution was then treated with HCl (1 M in Et₂O; 100 mL) and stirred at room temp. for 5 min. The resulting dark pink solid (7.04 g, 24.1 mmol) was removed by filtration from solution and stored under anaerobic conditions at 0° C. prior to use: ¹H NMR (DMSO-d₆) δ 2.41 (s, 3H), 2.78 (d, J=4.4 Hz, 3H), 4.93 (brs, 2H), 7.19 (dd, J=8.5, 2.6 Hz, 1H), 7.23 (dd, J=5.5, 2.6 Hz, 1H), 7.26 (d, J=2.6 Hz, 1H), 7.55 (d, J=2.6 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 8.55 (d, J=5.9 Hz, 1H), 8.99 (q, J=4.8 Hz, 1H).

-   A6. General Method for the Synthesis of Anilines from     Hydroxyanilines by N-Protection, Nucleophilic Aromatric Substitution     and Deprotection. Synthesis of     4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline

Step 1: Synthesis of 3-Chloro-4-(2,2,2-trifluoroacetylamino)phenol

Iron (3.24 g, 58.00 mmol) was added to stirring TFA (200 mL). To this slurry was added 2-chloro-4-nitrophenol (10.0 g, 58.0 mmol) and trifluoroacetic anhydride (20 mL). This gray slurry was stirred at room temp. for 6 d. The iron was filtered from solution and the remaining material was concentrated under reduced pressure. The resulting gray solid was dissolved in water (20 mL). To the resulting yellow solution was added a saturated NaHCO₃ solution (50 mL). The solid which precipitated from solution was removed. The filtrate was slowly quenched with the sodium bicarbonate solution until the product visibly separated from solution (determined was using a mini work-up vial). The slightly cloudy yellow solution was extracted with EtOAc (3×125 mL). The combined organic layers were washed with a saturated NaCl solution (125 mL), dried (MgSO₄) and concentrated under reduced pressure. The ¹H NMR (DMSO-d₆) indicated a 1:1 ratio of the nitrophenol starting material and the intended product 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol. The crude material was taken on to the next step without further purification.

Step 2: Synthesis of 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-trifluoro)acetamide

A solution of crude 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol (5.62 g, 23.46 mmol) in dry dimethylacetamide (50 mL) was treated with potassium tert-butoxide (5.16 g, 45.98 mmol) and the brownish black mixture was stirred at room temp. until the flask had cooled to room temp. The resulting mixture was treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step 3b; 1.99 g, 11.7 mmol) and heated at 100° C. under argon for 4 d. The black reaction mixture was cooled to room temp. and then poured into cold water (100 mL). The mixture was extracted with EtOAc (3×75 mL) and the combined organic layers were concentrated under reduced pressure. The residual brown oil was purified by column chromatography (gradient from 20% EtOAc/pet. ether to 40% EtOAc/pet. ether) to yield 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-trifluoro)acetamide as a yellow solid (8.59 g, 23.0 mmol).

Step 3. Synthesis of 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline

A solution of crude 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-trifluoro)acetamide (8.59 g, 23.0 mmol) in dry 4-dioxane (20 mL) was treated with a 1N NaOH solution (20 mL). This brown solution was allowed to stir for 8 h. To this solution was added EtOAc (40 mL). The green organic layer was extracted with EtOAc (3×40 mL) and the solvent was concentrated to yield 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline as a green oil that solidified upon standing (2.86 g, 10.30 mmol): ¹H NMR (DMSO-d₆) δ 2.77 (d, J=4.8 Hz, 3H), 5.51 (s, 2H), 6.60 (dd, J=8.5, 2.6 Hz, 1H), 6.76 (d, J=2.6 Hz, 1H), 7.03 (d, J=8.5 Hz, 1 H), 7.07 (dd, J=5.5, 2.6, Hz, 1H), 7.27 (d, J=2.6 Hz, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.75 (q, J=4.8, 1H).

-   A7. General Method for the Deprotection of an Acylated Aniline.     Synthesis of 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline

A suspension of 3-chloro-6-(N-acetyl)-4-(trifluoromethyl)anisole (4.00 g, 14.95 mmol) in a 6M HCl solution (24 mL) was heated at the reflux temp. for 1 h. The resulting solution was allowed to cool to room temp. during which time it solidified slightly. The resulting mixture was diluted with water (20 mL) then treated with a combination of solid NaOH and a saturated NaHCO₃ solution until the solution was basic. The organic layer was extracted with CH₂Cl₂ (3×50 mL). The combined organics were dried (MgSO₄) and concentrated under reduced pressure to yield 4-chloro-2-methoxy-5-(trifluoromethyl)aniline as a brown oil (3.20 g, 14.2 mmol): ¹H NMR (DMSO-d₆) δ 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H).

-   A8. General Method for Synthesis of ω-Alkoxy-ω-carboxyphenyl     Anilines. Synthesis of     4-(3-(N-Methylcarbamoly)-4-methoxyphenoxy)aniline.

Step 1. 4-(3-Methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene:

To a solution of 4-(3-carboxy-4-hydroxyphenoxy)-1-nitrobenzene (prepared from 2,5-dihydroxybenzoic acid in a manner analogous to that described in Method A13, Step 1, 12 mmol) in acetone (50 mL) was added K₂CO₃ (5 g) and dimethyl sulfate (3.5 mL). The resulting mixture was heated at the reflux temp. overnight, then cooled to room temp. and filtered through a pad of Celite®. The resulting solution was concentrated under reduced pressure, absorbed onto SiO₂, and purified by column chromatography (50% EtOAc/50% hexane) to give 4-(3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene as a yellow powder (3 g): mp 115-118° C.

Step 2. 4-(3Carboxy-4-methoxyphenoxy)-1-nitrobenzene:

A mixture of 4-(3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene (1.2 g), KOH (0.33 g) and water (5 mL) in MeOH (45 mL) was stirred at room temp. overnight and then heated at the reflux temp. for 4 h. The resulting mixture was cooled to room temp. and concentrated under reduced pressure. The residue was dissolved in water (50 mL), and the aqueous mixture was made acidic with a 1N HCl solution. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSO₄) and concentrated under reduced pressure to give 4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (1.04 g).

Step 3. 4-(3-(N-Methylcarbamoly)-4-methoxyphenoxy)-1-nitrobenzene:

To a solution of 4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (0.50 g, 1.75 mmol) in CH₂Cl₂ (12 mL) was added SOCl₂ (0.64 mL, 8.77 mmol) in portions. The resulting solution was heated at the reflux temp. for 18 h, cooled to room temp., and concentrated under reduced pressure. The resulting yellow solids were dissolved in CH₂Cl₂ (3 mL) then the resulting solution was treated with a methylamine solution (2.0 M in THF, 3.5 mL, 7.02 mmol) in portions (CAUTION: gas evolution), and stirred at room temp. for 4 h. The resulting mixture was treated with a 1N NaOH solution, then extracted with CH₂Cl₂ (25 mL). The organic layer was dried (Na₂SO₄) and concentrated under reduced pressure to give 4-(3-(N-methylcarbamoly)-4-methoxyphenoxy)-1-nitrobenzene as a yellow solid (0.50 g, 95%).

Step 4. 4-(3-(N-Methylcarbamoly)-4-methoxyphenoxy)aniline:

A slurry of 4-(3-(N-methylcarbamoly)-4-methoxyphenoxy)-1-nitrobenzene (0.78 g, 2.60 mmol) and 10% Pd/C (0.20 g) in EtOH (55 mL) was stirred under 1 atm of H₂ (balloon) for 2.5 d, then was filtered through a pad of Celite®. The resulting solution was concentrated under reduced pressure to afford 4-(3-(N-methylcarbamoly)-4-methoxyphenoxy)aniline as an off-white solid (0.68 g, 96%): TLC (0.1% Et₃N/99.9% EtOAc) R_(f)0.36.

-   A9. General Method for Preparation of ω-Akylphthalimide-containing     Anilines. Synthesis of     5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione

Step 1. Synthesis of 5-(4-Nitrophenoxy)-2-methylisoindoline-1,3-dione:

A slurry of 5-(4-nitrophenoxy)isoindoline-1,3-dione (A3 Step 2; 1.0 g, 3.52 mmol) and NaH (0.13 g, 5.27 mmol) in DMF (15 mL) was stirred at room temp. for 1 h, then treated with methyl iodide (0.3 mL, 4.57 mmol). The resulting mixture was stirred at room temp. overnight, then was cooled to ° C. and treated with water (10 mL). The resulting solids were collected and dried under reduced pressure to give 5-(4-nitrophenoxy)-2-methylisoindoline-1,3-dione as a bright yellow solid (0.87 g, 83%): TLC (35% EtOAc/65% hexane) R_(f)0.61.

Step 2. Synthesis of 5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione:

A slurry of nitrophenoxy)-2-methylisoindoline-1,3-dione (0.87 g, 2.78 mmol) and 10% Pd/C (0.10 g) in MeOH was stirred under 1 atm of H₂ (balloon) overnight. The resulting mixture was filtered through a pad of Celite® and concentrated under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 mL) and filtered through a plug of SiO₂ (60% EtOAc/40% hexane) to afford 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione as a yellow solid (0.67 g, 86%): TLC (40% EtOAc/60% hexane) R_(f)0.27.

-   A10. General Method for Synthesis of ω-Carbamoylaryl Anilines     Through Reaction of ω-Alkoxycarbonylaryl Precursors with Amines.     Synthesis of     4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline

Step 1. Synthesis of 4-Chloro-2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridine

To a solution of methyl 4-chloropyridine-2-carboxylate HCl salt (Method A2, Step 2; 1.01 g, 4.86 mmol) in THF (20 mL) was added 4-(2-aminoethyl)morpholine (2.55 mL, 19.4 mmol) dropwise and the resulting solution was heated at the reflux temp. for 20 h, cooled to room temp., and treated with water (50 mL). The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSO₄) and concentrated under reduced pressure to afford 4-chloro-2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridine as a yellow oil (1.25 g, 95%): TLC (10% MeOH/90% EtOAc) R_(f)0.50.

Step 2. Synthesis of 4-(2-(N-(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline.

A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium tert-butoxide (0.53 g, 4.75 mol) in DMF (8 mL) was stirred at room temp. for 2 h, then was sequentially treated with 4-chloro-2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridine (1.22 g, 4.52 mmol) and K₂CO₃ (0.31 g, 2.26 mmol). The resulting mixture was heated at 75° C. overnight, cooled to room temp., and separated between EtOAc (25 mL) and a saturated NaCl solution (25 mL). The aqueous layer was back extracted with EtOAc (25 mL). The combined organic layers were washed with a saturated NaCl solution (3×25 mL) and concentrated under reduced pressure. The resulting brown solids were purified by column chromatography (58 g; gradient from 100% EtOAc to 25% MeOH/75% EtOAc) to afford 4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline (1.0 g, 65%): TLC (10% MeOH/90% EtOAc) R_(f)0.32.

-   A11. General Method for the Reduction of Nitroarenes to Arylamines.     Synthesis of 4-(3-Carboxyphenoxy)aniline.

A slurry of 4-(3-carboxyphenoxy)-1-nitrobenzene (5.38 g, 20.7 mmol) and 10% Pd/C (0.50 g) in MeOH (120 mL) was stirred under an H₂ atmosphere (balloon) for 2 d. The resulting mixture was filtered through a pad of Celite®, then concentrated under reduced pressure to afford 4-(3-carboxyphenoxy)aniline as a brown solid (2.26 g, 48%): TLC (10% MeOH/90% CH₂Cl₂) R_(f)0.44 (streaking).

-   A12. General Method for the Synthesis of Isoindolinone-Containing     Anilines. Synthesis of 4-(1-Oxoisoindolin-5-yloxy)aniline.

Step 1. Synthesis of 5-hydroxyisoindolin-1-one

To a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 mL) was slowly added zinc dust (47.6 g, 729 mmol) in portions, then the mixture was heated at the reflux temp. for 40 min., filtered hot, and concentrated under reduced pressure. The reaction was repeated on the same scale and the combined oily residue was purified by column chromatography (1.1 Kg SiO₂; gradient from 60% EtOAc/40% hexane to 25% MeOH/75% EtOAc) to give 5-hydroxyisoindolin-1-one (3.77 g): TLC (100% EtOAc) R_(f)0.17; HPLC ES-MS m/z 150 ((M+H)⁺).

Step 2. Synthesis of 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene

To a slurry of NaH (0.39 g, 16.1 mmol) in DMF at 0° C. was added 5-hydroxyisoindolin-1-one (2.0 g, 13.4 mmol) in portions. The resulting slurry was allowed to warm to room temp. and was stirred for 45 min., then 4-fluoro-1-nitrobenzene was added and then mixture was heated at 70° C. for 3 h. The mixture was cooled to 0° C. and treated with water dropwise until a precipitate formed. The resulting solids were collected to give 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) R_(f)0.35.

Step 3. Synthesis of 4-(1-oxoisoindolin-5-yloxy)aniline

A slurry of 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene (2.12 g, 7.8 mmol) and 10% Pd/C (0.20 g) in EtOH (50 mL) was stirred under an H₂ atmosphere (balloon) for 4 h, then filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford 4-(1-oxoisoindolin-5-yloxy)aniline as a dark yellow solid: TLC (100% EtOAc) R_(f)0.15.

-   A13. General Method for the Synthesis of ω-Carbamoyl Anilines via     EDCI-Mediated Amide Formation Followed by Nitroarene Reduction.     Synthesis of 4-(3-N-Methylcarbamoylphenoxy)aniline.

Step 1. Synthesis of 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene

A mixture of 4-fluoro-1-nitrobenzene (16 mL, 150 mmol), ethyl 3-hydroxybenzoate 25 g, 150 mmol) and K₂CO₃ (41 g, 300 mmol) in DMF (125 mL) was heated at the reflux temp. overnight, cooled to room temp. and treated with water (250 mL). The resulting mixture was extracted with EtOAc (3×150 mL). The combined organic phases were sequentially washed with water (3×100 mL) and a saturated NaCl solution (2×100 mL), dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by column chromatography (10% EtOAc/90% hexane) to afford 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene as an oil (38 g).

Step 2. Synthesis of 4-(3-carboxyphenoxy)-1-nitrobenzene

To a vigorously stirred mixture of 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene (5.14 g, 17.9 mmol) in a 3:1 THlF/water solution (75 mL) was added a solution LiOH.H₂O (1.50 g, 35.8 mmol) in water (36 mL). The resulting mixture was heated at 50° C. overnight, then cooled to room temp., concentrated under reduced pressure, and adjusted to pH 2 with a 1M HCl solution. The resulting bright yellow solids were removed by filtration and washed with hexane to give 4-(3-carboxyphenoxy)-1-nitrobenzene (4.40 g, 95%).

Step 3. Synthesis of 4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene

A mixture of 4-(3-carboxyphenoxy)-1-nitrobenzene (3.72 g, 14.4 mmol), EDCI.HCl (3.63 g, 18.6 mmol), N-methylmorpholine (1.6 mL, 14.5 mmol) and methylamine (2.0 M in THF; 8 mL, 16 mmol) in CH₂Cl₂ (45 mL) was stirred at room temp. for 3 d, then concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and the resulting mixture was extracted with a 1M HCl solution (50 mL). The aqueous layer was back-extracted with EtOAc (2×50 mL). The combined organic phases were washed with a saturated NaCl solution (50 mL), dried (Na₂SO₄), and concentrated under reduced pressure to give 4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene as an oil (1.89 g).

Step 4. Synthesis of 4-(3-(N-methylcarbamoyl)phenoxy)aniline

A slurry of 4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene (1.89 g, 6.95 mmol) and 5% Pd/C (0.24 g) in EtOAc (20 mL) was stirred under an H₂ atm (balloon) overnight. The resulting mixture was filtered through a pad of Celite® and concentrated under reduced pressure. The residue was purified by column chromatography (5% MeOH/95% CH₂Cl₂). The resulting oil solidified under vacuum overnight to give 4-(3-(N-methylcarbamoyl)phenoxy)aniline as a yellow solid (0.95 g, 56%).

-   A14. General Method for the Synthesis of ω-Carbamoyl Anilines via     EDCI-Mediated Amide Formation Followed by Nitroarene Reduction.     Synthesis of 4-3-(5-Methylcarbamoyl)pyridyloxy)aniline

Step 1. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene

To a slurry of NaH (0.63 g, 26.1 mmol) in DMF (20 mL) was added a solution of methyl 5-hydroxynicotinate (2.0 g, 13.1 mmol) in DMF (10 mL). The resulting mixture was added to a solution of 4-fluoronitrobenzene (1.4 mL, 13.1 mmol) in DMF (10 mL) and the resulting mixture was heated at 70° C. overnight, cooled to room temp., and treated with MeOH (5 mL) followed by water (50 mL). The resulting mixture was extracted with EtOAc (100 mL). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc/70% hexane) to afford 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.60 g).

Step 2. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline

A slurry of 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.60 g, 2.20 mmol) and 10% Pd/C in MeOH/EtOAc was stirred under an H₂ atmosphere (balloon) for 72 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 10% EtOAc/90% hexane to 30% EtOAc/70% hexane to 50% EtOAc/50% hexane) to afford 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline (0.28 g, 60%): ¹H NMR (CDCl₃) δ 3.92 (s, 3H), 6.71 (d, 2H), 6.89 (d, 2H), 7.73 (, 1H), 8.51 (d, 1H), 8.87 (d, 1H).

-   A15. Synthesis of an Aniline via Electrophilic Nitration Followed by     Reduction. Synthesis of 4-(3-Methylsulfamoylphenoxy)aniline.

Step 1. Synthesis of N-methyl-3-bromobenzenesulfonamide

To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF (15 mL) at 0° C. was added methylamine (2.0 M in THF; 28 mL, 56 mmol). The resulting solution was allowed to warm to room temp. and was stirred at room temp. overnight. The resulting mixture was separated between EtOAc (25 mL) and a 1 M HCl solution (25 mL). The aqueous phase was back-extracted with EtOAc (2×25 mL). The combined organic phases were sequentially washed with water (2×25 mL) and a saturated NaCl solution (25 mL), dried (MgSO₄) and concentrated under reduced pressure to give N-methyl-3-bromobenzenesulfonamide as a white solid (2.8 g, 99%).

Step 2. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)benzene

To a slurry of phenol (1.9 g, 20 mmol), K₂CO₃ (6.0 g, 40 mmol), and CuI (4 g, 20 mmol) in DMF (25 mL) was added N-methyl-3-bromobenzenesulfonamide (2.5 g, 10 mmol), and the resulting mixture was stirred at the reflux temp. overnight, cooled to room temp., and separated between EtOAc (50 mL) and a 1 N HCl solution (50 mL). The aqueous layer was back-extracted with EtOAc (2×50 mL). The combined organic phases were sequentially washed with water (2×50 mL) and a saturated NaCl solution (50 mL), dried (MgSO₄), and concentrated under reduced pressure. The residual oil was purified by column chromatography (30% EtOAc/70% hexane) to give 4-(3-(N-methylsulfamoyl)phenyloxy)benzene (0.30 g).

Step 3. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)-1-nitrobenzene

To a solution of 4-(3-(N-methylsulfamoyl)phenyloxy)benzene (0.30 g, 1.14 mmol) in TFA (6 mL) at −10° C. was added NaNO₂ (0.097 g, 1.14 mmol) in portions over 5 min. The resulting solution was stirred at −10° C. for 1 h, then was allowed to warm to room temp., and was concentrated under reduced pressure. The residue was separated between EtOAc (10 mL) and water (10 mL). The organic phase was sequentially washed with water (10 mL) and a saturated NaCl solution (10 mL), dried (MgSO₄) and concentrated under reduced pressure to give 4-(3-(N-methylsulfamoyl)phenyloxy)-1-nitrobenzene (0.20 g). This material carried on to the next step without further purification.

Step 4. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)anillne

A slurry of 4-(3-(N-methylsulfamoyl)phenyloxy)-1-nitrobenzene (0.30 g) and 10% Pd/C (0.030 g) in EtOAc (20 mL) was stirred under an H₂ atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAcn70% hexane) to give 4-(3-(N-methylsulfamoyl)phenyloxy)aniline (0.070 g).

A16. Modification of ω-ketones. Synthesis of 4-(4-(1-(N-methoxy)iminoethyl)phenoxyaniline HCl salt.

To a slurry of 4-(4-acetylphenoxy)aniline HCl salt (prepared in a manner analogous to Method A13, step 4; 1.0 g, 3.89 mmol) in a mixture of EtOH (10 mL) and pyridine (1.0 mL) was added O-methylhydroxylamine HCl salt (0.65 g, 7.78 mmol, 2.0 equiv.). The resulting solution was heated at the reflux temperature for 30 min, cooled to room temperature and concentrated under reduced pressure. The resulting solids were triturated with water (10 mL) and washed with water to give 4-(4-(1-(N-methoxy)iminoethyl) phenoxyaniline HCl salt as a yellow solid (0.85 g): TLC (50% EtOAc/50% pet. ether) R_(f)0.78; ¹H NMR (DMSO-d₆) δ 3.90 (s, 3H), 5.70 (s, 3H); HPLC-MS m/z 257 ((M+H)⁺).

-   A17. Synthesis of N-(ω-Silyloxyalkyl)amides. Synthesis of     4-(4-(2-(N-(2-Triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline.

Step 1. 4-Chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide

To a solution of 4-chloro-N-(2-hydroxyethyl)pyridine-2-carboxamide (prepared in a manner analogous to Method A2, Step 3b; 1.5 g, 7.4 mmol) in anh DMF (7 mL) was added triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 equiv.) and imidazole (1.12 g, 16.4 mmol, 2.2 equiv.). The resulting yellow solution was stirred for 3 h at room temp, then was concentrated under reduced pressure. The residue was separated between water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic phases were dried (MgSO₄), and concentrated under reduced pressure to afford 4-chloro-2-(N-(2-triisopropylsilyloxy)ethyl)pyridinecarboxamide as an orange oil (2.32 g, 88%). This material was used in the next step without further purification.

Step 2. 4-(4-(2-(N-(2-Triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline

To a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in anh DMF (8 mL) was added potassium tert-butoxide (0.67 g, 6.0 mmol, 1.0 equiv.) in one portion causing an exotherm. When this mixture had cooled to room temperature, a solution of 4-chloro-2-(N-(2-triisopropylsilyloxy)ethyl)pyridinecarboxamide (2.32 g, 6 mmol, 1 equiv.) in DMF (4 mL) was added followed by K₂CO₃ (0.42 g, 3.0 mmol, 0.50 equiv.). The resulting mixture was heated at 80° C. overnight. An additional portion of potassium tert-butoxide (0.34 g, 3 mmol, 0.5 equiv.) was then added and the mixture was stirred at 80° C. an additional 4 h. The mixture was cooled to 0° C. with an ice/water bath, then water (approx. 1 mL) was slowly added dropwise. The organic layer was extracted with EtOAc (3×10 mL). The combined organic layers were washed with a saturated NaCl solution (20 mL), dried (MgSO₄) and concentrated under reduced pressure. The brown oily residue was purified by column chromatography (SiO₂; 30% EtOAc/70% pet ether) to afford 4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline as a clear light brown oil (0.99 g, 38%).

-   A18. Synthesis of 2-Pryidinecarboxylate Esters via Oxidation of     2-Methylpyridines. Synthesis of     4-(5-(2-methoxycarbonyl)pyridyloxy)aniline.

Step 1. 4-(5-(2-Methyl)pyridyloxy)-1-nitrobenzene.

A mixture of 5-hydroxy-2-methylpyridine (10.0 g, 91.6 mmol), 1-fluoro-4-nitrobenzene (9.8 mL, 91.6 mmol, 1.0 equiv.), K₂CO₃ (25 g, 183 mmol, 2.0 equiv.) in DMF (100 mL) was heated at the reflux temperature overnight. The resulting mixture was cooled to room temperature, treated with water (200 mL), and extracted with EtOAc (3×100 mL). The combined organic layers were sequentially washed with water (2×100 mL) and a saturated NaCl solution ((100 mL), dried (MgSO₄) and concentrated under reduced pressure to give 4-(5-(2-methyl)pyridyloxy)-1-nitrobenzene as a brown solid (12.3 g).

Step 2. Synthesis of 4-(5-(2-Methoxycarbonyl)pyridyloxy)-1-nitrobenzene.

A mixture of 4-(5-(2-methyl)pyridyloxy)-1-nitrobenzene (1.70 g, 7.39 mmol) and selenium dioxide (2.50 g, 22.2 mmol, 3.0 equiv.) in pyridine (20 mL) was heated at the reflux temperature for 5 h, then cooled to room temperature. The resulting slurry was filtered, then concentrated under reduced pressure. The residue was dissolved in MeOH (100 mL). The solution was treated with a conc HCl solution (7 mL), then heated at the reflux temperature for 3 h, cooled to room temperature and concentrated under reduced pressure. The residue was separated between EtOAc (50 mL) and a 1N NaOH solution (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were sequentially washed with water (2×50 mL) and a saturated NaCl solution (50 mL), dried (MgSO₄) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂; 50% EtOAc/50% hexane) to afford 4-(5-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.70 g).

Step 3. Synthesis of 4-(5-(2-Methoxycarbonyl)pyridyloxy)aniline.

A slurry of 4-(5-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.50 g) and 10% Pd/C (0.050 g) in a mixture of EtOAc (20 mL) and MeOH (5 mL) was placed under a H₂ atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of Celite®, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂; 70% EtOAc/30% hexane) to give 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline (0.40 g).

-   A19. Synthesis of ω-Sulfonylphenyl Anilines. Synthesis of     4-(4-Methylsulfonylphenyoxy)aniline.

-   Step 1. 4-(4-Methylsulfonylphenoxy)-1-nitrobenzene: To a solution of     4-(4-methylthiophenoxy)-1-nitrobenzene (2.0 g, 7.7 mmol) in CH₂Cl₂     (75 mL) at 0° C. was slowly added m-CPBA (57-86%, 4.0 g), and the     reaction mixture was stirred at room temperature for 5 h. The     reaction mixture was treated with a 1N NaOH solution (25 mL). The     organic layer was sequentially washed with a 1N NaOH solution (25     mL), water (25 mL) and a saturated NaCl solution (25 mL), dried     (MgSO₄), and concentrated under reduced pressure to give     4-(4-methylsulfonylphenoxy)-1-nitrobenzene as a solid (2.1 g). -   Step 2. 4-(4-Methylsulfonylphenoxy)-1-aniline:     4-(4-Methylsulfonylphenoxy)-1-nitrobenzene was reduced to the     aniline in a manner analogous to that described in Method A18, step     3. -   B. Synthesis of Urea Precursors -   B1. General Method for the Synthesis of Isocyanates from Anilines     Using CDI. Synthesis of 4-Bromo-3-(trifluoromethyl)phenyl     Isocyanate.

Step 1. Synthesis of 4-bromo-3-(trifluoromethyl)aniline HCl salt

To a solution of 4-bromo-3-(trifluoromethyl)aniline (64 g, 267 mmol) in Et₂O (500 mL) was added an HCl solution (1 M in Et₂O; 300 mL) dropwise and the resulting mixture was stirred at room temp. for 16 h. The resulting pink-white precipitate was removed by filtration and washed with Et₂O (50 mL) and to afford 4-bromo-3-(trifluoromethyl)aniline HCl salt (73 g, 98%).

Step 2. Synthesis of 4-bromo-3-(trifluoromethyl)phenyl isocyanate

A suspension of 4-bromo-3-(trifluoromethyl)aniline HCl salt (36.8 g, 133 mmol) in toluene (278 mL) was treated with trichloromethyl chloroformate dropwise and the resulting mixture was heated at the reflux temp. for 18 h. The resulting mixture was concentrated under reduced pressure. The residue was treated with toluene (500 mL), then concentrated under reduced pressure. The residue was treated with CH₂Cl₂ (500 mL), then concentrated under reduced pressure. The CH₂Cl₂ treatment/concentration protocol was repeated and resulting amber oil was stored at −20° C. for 16 h, to afford 4-bromo-3-(trifluoromethyl)phenyl isocyanate as a tan solid (35.1 g, 86%): GC-MS m/z 265 (M⁺).

-   C. Methods of Urea Formation -   C1a. General Method for the Synthesis of Ureas by Reaction of an     Isocyanate with an Aniline. Synthesis of     N-(4-Chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)     Urea

A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (14.60 g, 65.90 mmol) in CH₂Cl₂ (35 mL) was added dropwise to a suspension of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (Method A2, Step 4; 16.0 g, 65.77 mmol) in CH₂Cl₂ (35 mL) at 0° C. The resulting mixture was stirred at room temp. for 22 h. The resulting yellow solids were removed by filtration, then washed with CH₂Cl₂ (2×30 mL) and dried under reduced pressure (approximately 1 mmHg (13.2×10⁻⁴ atm)) to afford N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as an off-white solid (28.5 g, 93%): mp 207-209° C.; ¹H-NMR (DMSO-d₆) δ 2.77 (d, J=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J=2.5 Hz, 1H), 7.62 (m, 4H), 8.11 (d, J=2.5 Hz, 1H), 8.49 (d, J=.5.5 Hz, 1H), 8.77 (brd, 1 H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m/z 465 ((M+H)⁺).

-   C1b. General Method for the Synthesis of Ureas by Reaction of an     Isocyanate with an Aniline. Synthesis of     N-(4-Bromo-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)     Urea

A solution of 4-bromo-3-(trifluoromethyl)phenyl isocyanate (Method B1, Step 2; 8.0 g, 30.1 mmol) in CH₂Cl₂ (80 mL) was added dropwise to a solution of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (Method A2, Step 4; 7.0 g, 28.8 mmol) in CH₂Cl₂ (40 mL) at 0° C. The resulting mixture was stirred at room temp. for 16 h. The resulting yellow solids were removed by filtration, then washed with CH₂Cl₂ (2×50 mL) and dried under reduced pressure (approximately 1 mmHg (13.2×10⁻⁴ atm)) at 40° C. to afford N-(4-bromo-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a pale-yellow solid (13.2 g, 90%): mp 203-205° C.; ¹H-NMR (DMSO-d₆) δ 2.77 (d, J=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J=2.5 Hz, 1H), 7.58 (m, 3H), 7.77 (d, J=8.8 Hz, 1H), 8.11 (d, J=2.5 Hz, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.77 (brd, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m/z 509 ((M+H)⁺).

-   C1c. General Method for the Synthesis of Ureas by Reaction of an     Isocyanate with an Aniline. Synthesis of     N-(4-Chloro-3-(trifluoromethyl)phenyl)-N′-(2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)     Urea

A solution of 2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))aniline (Method A5; 0.11 g, 0.45 mmol) in CH₂Cl₂ (1 mL) was treated with Et₃N (0.16 mL) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.45 mmol). The resulting brown solution was stirred at room temp. for 6 d, then was treated with water (5 mL). The aqueous layer was back-extracted with EtOAc (3×5 mL). The combined organic layers were dried (MgSO₄) and concentrated under reduced pressure to yield N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea as a brown oil (0.11 g, 0.22 mmol): ¹H NMR (DMSO-d₆) δ 2.27 (s, 3H), 2.77 (d, J=4.8 Hz, 3H), 7.03 (dd, J=8.5, 2.6 Hz, 1H), 7.11 (d, J=2.9 Hz, 1H), 7.15 (dd, J=5.5, 2.6, Hz, 1H), 7.38 (d, J=2.6 Hz, 1H), 7.62 (app d, J=2.6 Hz, 2H), 7.84 (d, J=8.8 Hz, 1H), 8.12 (s, 1H), 8.17 (s, 1H); 8.50 (d, J=5.5 Hz, 1H), 8.78 (q, J=5.2, 1H), 9.52 (s, 1H); HPLC ES-MS m/z 479 ((M+H)⁺).

-   C1d. General Method for the Synthesis of Ureas by Reaction of an     Isocyanate with an Aniline. Synthesis of     N-(4-Chloro-3-(trifluoromethyl)phenyl)-N′-(4-aminophenyl) Urea

To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (2.27 g, 10.3 mmol) in CH₂Cl₂ (308 mL) was added p-phenylenediamine (3.32 g, 30.7 mmol) in one part. The resulting mixture was stirred at room temp. for 1 h, treated with CH₂Cl₂ (100 mL), and concentrated under reduced pressure. The resulting pink solids were dissolved in a mixture of EtOAc (110 mL) and MeOH (15 mL), and the clear solution was washed with a 0.05 N HCl solution. The organic layer was concentrated under reduced pressure to afford impure N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-aminophenyl) urea (3.3 g): TLC (100% EtOAc) R_(f)0.72.

-   C1e. General Method for the Synthesis of Ureas by Reaction of an     Isocyanate with an Aniline. Synthesis of     N-(4-Chloro-3-(trifluoromethyl)phenyl)-N′-(4-ethoxycarbonylphenyl)     Urea

To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 mmol) in CH₂Cl₂ (30 mL) was added 4-chloro-3-(trifluoromethyl)aniline (3.21 g, 16.4 mmol), and the solution was stirred at room temp. overnight. The resulting slurry was diluted with CH₂Cl₂ (50 mL) and filtered to afford N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-ethoxycarbonylphenyl) urea as a white solid (5.93 g, 97%): TLC (40% EtOAc/60% hexane) R_(f)0.44.

-   C1f. General Method for the Synthesis of Ureas by Reaction of an     Isocyanate with an Aniline. Synthesis of     N-(4-Chloro-3-(trifluoromethyl)phenyl)-N′-(3-carboxyphenyl) Urea

To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (1.21 g, 5.46 mmol) in CH₂Cl₂ (8 mL) was added 4-(3-carboxyphenoxy)aniline (Method A11; 0.81 g, 5.76 mmol) and the resulting mixture was stirred at room temp. overnight, then treated with MeOH (8 mL), and stirred an additional 2 h. The resulting mixture was concentrated under reduced pressure. The resulting brown solids were triturated with a 1:1 EtOAc/hexane solution to give N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(3-carboxyphenyl) urea as an off-white solid (1.21 g, 76%).

-   C2a. General Method for Urea Synthesis by Reaction of an Aniline     with N,N′-Carbonyl Diimidazole Followed by Addition of a Second     Aniline. Synthesis of     N-(2-Methoxy-5-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)     Urea

To a solution of 2-methoxy-5-(trifluoromethyl)aniline (0.15 g) in anh CH₂Cl₂ (15 mL) at 0° C. was added CDI (0.13 g). The resulting solution was allowed to warm to room temp. over 1 h, was stiffed at room temp. for 16 h, then was treated with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.18 g). The resulting yellow solution was stirred at room temp. for 72 h, then was treated with H₂O (125 mL). The resulting aqueous mixture was extracted with EtOAc (2×150 mL). The combined organics were washed with a saturated NaCl solution (100 mL), dried (MgSO₄) and concentrated under reduced pressure. The residue was triturated (90% EtOAc/10% hexane). The resulting white solids were collected by filtration and washed with EtOAc. The filtrate was concentrated under reduced pressure and the residual oil purified by column chromatography (gradient from 33% EtOAc/67% hexane to 50% EtOAc/50% hexane to 100% EtOAc) to give N-(2-methoxy-5-(tifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pynidyloxy)phenyl) urea as a light tan solid (0.098 g, 30%): TLC (100% EtOAc) R_(f)0.62; ¹H NMR (DMSO-d₆) δ 2.76 (d, J=4.8 Hz, 3H), 3.96 (s, 3H), 7.1-7.6 and 8.4-8.6 (m, 11H), 8.75 (d, J=4.8 Hz, 1H), 9.55 (s, 1 H); FAB-MS m/z 461 ((M+H)⁺).

-   C2b. General Method for Urea Synthesis by Reaction of an Aniline     with N,N′-Carbonyl Diimidazole Followed by Addition of a Second     Aniline. Symmetrical Urea's as Side Products of a N,N′-Carbonyl     Diimidazole Reaction Procedure. Synthesis of     Bis(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) Urea

To a stirring solution of 3-amino-2-methoxyquinoline (0.14 g) in anhydrous CH₂Cl₂ (15 mL) at 0 C. was added CDI (0.13 g). The resulting solution was allowed to warm to room temp. over 1 h then was stirred at room temp. for 16 h. The resulting mixture was treated with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.18 g). The resulting yellow solution stirred at room temp. for 72 h, then was treated with water (125 mL). The resulting aqueous mixture was extracted with EtOAc (2×150 mL). The combined organic phases were washed with a saturated NaCl solution (100 ml), dried (MgSO₄) and concentrated under reduced pressure. The residue was triturated (90% EtOAc/10% hexane). The resulting white solids were collected by filtration and washed with EtOAc to give bis(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea (0.081 g, 44%): TLC (100% EtOAc) R_(f)0.50; ¹H NMR (DMSO-d₆) δ 2.76 (d, J=5.1 Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d, J=5.4 Hz, 1H), 8.75 (d, J=4.8 Hz, 2H), 8.86 (s, 2H); HPLC ES-MS m/z 513 ((M+H)⁺).

-   C2c. General Method for the Synthesis of Ureas by Reaction of an     Isocyanate with an Aniline. Synthesis of     N-(2-Methoxy-5-(trifluoromethyl)phenyl-N′-(4-(1,3-dioxoisoindolin-5-yloxy)phenyl)     Urea

To a stirring solution of 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.47 mmol) in CH₂Cl₂ (1.5 mL) was added 5-(4-aminophenoxy)isoindoline-1,3-dione (Method A3, Step 3; 0.12 g, 0.47 mmol) in one portion. The resulting mixture was stirred for 12 h, then was treated with CH₂Cl₂ (10 mL) and MeOH (5 mL). The resulting mixture was sequentially washed with a 1N HCl solution (15 mL) and a saturated NaCl solution (15 mL), dried (MgSO₄) and concentrated under reduced pressure to afford N-(2-methoxy-5-(trifluoromethyl)phenyl-N′-(4-(1,3-dioxoisoindolin-5-yloxy)phenyl) urea as a white solid (0.2 g, 96%): TLC (70% EtOAc/30% hexane) R_(f)0.50; ¹H NMR (DMSO-d₆) δ 3.95 (s, 3H), 7.31- 7.10 (m, 6H), 7.57 (d, J=9.3 Hz, 2H), 7.80 (d, J=8.7 Hz, 1H), 8.53 (brs, 2H), 9.57 (s, 1H), 11.27 (brs, 1H); HPLC ES-MS 472.0 ((M+H)⁺, 100%).

-   C2d. General Method for Urea Synthesis by Reaction of an Aniline     with N,N′-Carbonyl Diinidazole Followed by Addition of a Second     Aniline. Synthesis of     N-(5-(tert-Butyl)-2-(2,5-dimethylpyrrolyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)     Urea

To a stirring solution of CDI (0.21 g, 1.30 mmol) in CH₂Cl₂ (2 mL) was added 5-(tert-butyl)-2-(2,5-dimethylpyrrolyl)aniline (Method A4, Step 2; 0.30 g, 1.24 mmol) in one portion. The resulting mixture was stirred at room temp. for 4 h, then 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.065 g, 0.267 mmol) was then added in one portion. The resulting mixture was heated at 36° C. overnight, then cooled to room temp. and diluted with EtOAc (5 mL). The resulting mixture was sequentially washed with water (15 mL) and a 1N HCl solution (15 mL), dried (MgSO₄), and filtered through a pad of silica gel (50 g) to afford N-(5-(tert-butyl)-2-(2,5-dimethylpyrrolyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a yellowish solid (0.033 g, 24%): TLC (40% EtOAc/60% hexane) R_(f)0.24; ¹H NMR (acetone-d₆) δ 1.37 (s, 9H), 1.89 (s, 6H), 2.89 (d, J=4.8 Hz, 3H), 5.83 (s, 2H), 6.87-7.20 (m, 6H), 7.17 (dd, 1H), 7.51-7.58 (m, 3H), 8.43 (d, J=5.4 Hz, 1H), 8.57 (d, J=2.1 Hz, 1H), 8.80 (brs, 1H); HPLC ES-MS 512 ((M+H)⁺, 100%).

-   C3. Combinatorial Method for the Synthesis of Diphenyl Ureas Using     Triphosgene

One of the anilines to be coupled was dissolved in dichloroethane (0.10 M). This solution was added to a 8 mL vial (0.5 mL) containing dichloroethane (1 mL). To this was added a bis(trichloromethyl) carbonate solution (0.12 M in dichloroethane, 0.2 mL, 0.4 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The vial was capped and heat at 80° C. for 5 h, then allowed to cool to room temp for approximately 10 h. The second aniline was added (0.10 M in dichloroethane, 0.5 mL, 1.0 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The resulting mixture was heated at 80° C. for 4 h, cooled to room temperature and treated with MeOH (0.5 mL). The resulting mixture was concentrated under reduced pressure and the products were purified by reverse phase HPLC.

-   C4. General Method for Urea Synthesis by Reaction of an Aniline with     Phosgene Followed by Addition of a Second Aniline. Synthesis of     N-(2-Methoxy-5-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)     Urea

To a stirring solution of phosgene (1.9 M in toluene; 2.07 mL0.21 g, 1.30 mmol) in CH₂Cl₂ (20 mL) at 0° C. was added anh pyridine (0.32 mL) followed by 2-methoxy-5-(trifluoromethyl)aniline (0.75 g). The yellow solution was allowed to warm to room temp during which a precipitate formed. The yellow mixture was stirred for 1 h, then concentrated under reduced pressure. The resulting solids were treated with anh toluene (20 mL) followed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (prepared as described in Method A2; 0.30 g) and the resulting suspension was heated at 80° C. for 20 h, then allowed to cool to room temp. The resulting mixture was diluted with water (100 mL), then was made basic with a saturated NaHCO₃ solution (2-3 mL). The basic solution was extracted with EtOAc (2×250 mL). The organic layers were separately washed with a saturated NaCl solution, combined, dried (MgSO₄), and concentrated under reduced pressure. The resulting pink-brown residue was dissolved in MeOH and absorbed onto SiO₂ (100 g). Column chromatography (300 g SiO₂; gradient from 1% Et₃N/33% EtOAc/66% hexane to 1% Et₃N/99% EtOAc to 1% Et₃N/20% MeOH/79% EtOAc) followed by concentration under reduced pressure at 45° C. gave a warm concentrated EtOAc solution, which was treated with hexane (10 mL) to slowly form crystals of N-(2-methoxy-5-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea (0.44 g): TLC (1% Et₃N/99% EtOAc) R_(f) 0.40.

-   D. Interconversion of Ureas -   D1a. Conversion of ω-Aminophenyl Ureas into ω-(Aroylamino)phenyl     Ureas. Synthesis of     N-(4-Chloro-3-((trifluoromethyl)phenyl)-N′-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl)     Urea

To a solution of N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-aminophenyl) urea (Method C1d; 0.050 g, 1.52 mmol), mono-methyl isophthalate (0.25 g, 1.38 mmol), HOBT.H₂O (0.41 g, 3.03 mmol) and N-methylmorpholine (0.33 mL, 3.03 mmol) in DMF (8 mL) was added EDCI.HCl (0.29 g, 1.52 mmol). The resulting mixture was stirred at room temp. overnight, diluted with EtOAc (25 mL) and sequentially washed with water (25 mL) and a saturated NaHCO₃ solution (25 mL). The organic layer was dried (Na₂SO₄) and concentrated under reduced pressure. The resulting solids were triturated with an EtOAc solution (80% EtOAc/20% hexane) to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl) urea (0.27 g, 43%): mp 121-122; TLC (80% EtOAc/20% hexane) R_(f)0.75.

-   D1b. Conversion of ω-Carboxyphenyl Ureas into     ω-(Arylcarbamoyl)phenyl Ureas. Synthesis of     N-(4-Chloro-3-((trifluoromethyl)phenyl)-N′-(4-(3-methylcarbamoylphenyl)carbamoylphenyl)     Urea

To a solution of N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(3-methylcarbamoylphenyl) carboxyaminophenyl) urea (0.14 g, 0.48 mmol), 3-methylcarbamoylaniline (0.080 g, 0.53 mmol), HOBT.H₂O (0.14 g, 1.07 mmol), and N-methylmorpholine (0.5 mL, 1.07 mmol) in DMF (3 mL) at 0° C. was added EDCI.HCl (0.10 g, 0.53 mmol). The resulting mixture was allowed to warm to room temp. and was stirred overnight. The resulting mixture was treated with water (10 mL), and extracted with EtOAc (25 mL). The organic phase was concentrated under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 mL) then filtered through a pad of silica gel (17 g, gradient from 70% EtOAc/30% hexane to 10% MeOH/90% EtOAc) to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(3-methylcarbamoylphenyl)carbamoylphenyl) urea as a white solid (0.097 g, 41%): mp 225-229; TLC (100% EtOAc) R_(f)0.23.

-   D1c. Combinatorial Approach to the Conversion of ω-Carboxyphenyl     Ureas into ω-(Arylcarbamoyl)phenyl Ureas. Synthesis of     N-(4-Chloro-3-((trifluoromethyl)phenyl)-N′-(4-(N-(3-(N-(3-pyridyl)carbamoyl)phenyl)carbamoyl)phenyl)     Urea

A mixture of N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(3-carboxyphenyl) urea (Method C1f; 0.030 g, 0.067 mmol) and N-cyclohexyl-N′-(methylpolystyrene)carbodiimide (55 mg) in 1,2-dichloroethane (1 mL) was treated with a solution of 3-aminopyridine in CH₂Cl₂ (1 M; 0.074 mL, 0.074 mmol). (In cases of insolubility or turbidity, a small amount of DMSO was also added.) The resulting mixture was heated at 36° C. overnight. Turbid reactions were then treated with THF (1 mL) and heating was continued for 18 h. The resulting mixtures were treated with poly(4-(isocyanatomethyl)styrene) (0.040 g) and the resulting mixture was stirred at 36° C. for 72 h, then cooled to room temp. and filtered. The resulting solution was filtered through a plug of silica gel (1 g). Concentration under reduced pressure afforded N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(N-(3-(N-(3-pyridyl)carbamoyl)phenyl)carbamoyl)phenyl) urea (0.024 g, 59%): TLC (70% EtOAc/30% hexane) R_(f)0.12.

-   D2. Conversion of ω-Carboalkoxyaryl Ureas into ω-Carbamoylaryl     Ureas. Synthesis of     N-(4-Chloro-3-((trifluoromethyl)phenyl)-N′-(4-(3-methylcarbamoylphenyl)carboxyaminophenyl)     Urea

To a sample of N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(3-carbomethoxyphenyl) carboxyaminophenyl) urea (0.17 g, 0.34 mmol) was added methylamine (2 M in THF; 1 mL, 1.7 mmol) and the resulting mixture was stirred at room temp. overnight, then concentrated under reduced pressure to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(3-methylcarbamoylphenyl)carboxyaminophenyl) urea as a white solid: mp 247; TLC (100% EtOAc) R_(f)0.35.

-   D3. Conversion of ω-Carboalkoxyaryl Ureas into ω-Carboxyaryl Ureas.     Synthesis of     N-(4-Chloro-3-((trifluoromethyl)phenyl)-N′-(4-carboxyphenyl) Urea

To a slurry of N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-ethoxycarbonylphenyl) urea (Method C1e; 5.93 g, 15.3 mmol) in MeOH (75 mL) was added an aqueous KOH solution (2.5 N, 10 mL, 23 mmol). The resulting mixture was heated at the reflux temp. for 12 h, cooled to room temp., and concentrated under reduced pressure. The residue was diluted with water (50 mL), then treated with a 1 N HCl solution to adjust the pH to 2 to 3. The resulting solids were collected and dried under reduced pressure to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-carboxyphenyl) urea as a white solid (5.05 g, 92%).

-   D4. General Method for the Conversion of (9-Alkoxy Esters into     ω-Alkyl Amides. Synthesis of     N-(4-Chloro-3-((trifluoromethyl)phenyl)-N′-((4-(3-(5-(2-dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl)     Urea

Step 1. Synthesis of N-(4-Chloro-3-(trifluoromethyl)phenyl)-N′-((4-(3-(5-carboxypyridyl) oxyphenyl) Urea

N-(4-Chloro-3-(trifluoromethyl)phenyl)-N′-((4-(3-(5-methoxycarbonylpyridyl)oxyphenyl) urea was synthesized from 4-chloro-3-(trifluoromethyl)phenyl isocyanate and 4-(3-(5-methoxycarbonylpyridyl) oxyaniline (Method A14, Step 2) in a manner analogous to Method C1a. A suspension of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-((4-(3-(5-methoxycarbonylpyridyl)oxyphenyl) urea (0.26 g, 0.56 mmol) in MeOH (10 mL) was treated with a solution of KOH (0.14 g, 2.5 mmol) in water (1 mL) and was stirred at room temp. for 1 h. The resulting mixture was adjusted to pH 5 with a 1 N HCl solution. The resulting precipitate was removed by filtration and washed with water. The resulting solids were dissolved in EtOH (10 mL) and the resulting solution was concentrated under reduced pressure. The EtOH/concentration procedure was repeated twice to give N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-((4-(3-(5-carboxypyridyl) oxyphenyl) urea (0.18 g, 71%).

Step 2. Synthesis of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-((4-(3-(5-(2-dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) urea

A mixture of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-((4-(3-(5-carboxypyridyl)oxyphenyl) urea (0.050 g, 0.011 mmol), N,N-dimethylethylenediamine (0.22 mg, 0.17 mmol), HOBT (0.028 g, 0.17 mmol), N-methylmorpholine (0.035 g, 0.28 mmol), and EDCI.HCl (0.032 g, 0.17 mmol) in DMF (2.5 mL) was stirred at room temp. overnight. The resulting solution was separated between EtOAc (50 mL) and water (50 mL). The organic phase was washed with water (35 mL), dried (MgSO₄) and concentrated under reduced pressure. The residue was dissolved in a minimal amount of CH₂Cl₂ (approximately 2 mL). The resulting solution was treated with Et₂O dropwise to give N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-((4-(3-(5-(2-dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) urea as a white precipitate (0.48 g, 84%: ¹H NMR (DMSO-d₆) δ 2.10 s, 6H), 3.26 (s, H), 7.03 (d, 2H), 7.52 (d, 2H), 7.60 (m, 3H), 8.05 (s, 1H), 8.43 (s, 1H), 8.58 (t, 1H), 8.69 (s, 1H), 8.90 (s, 1H), 9.14 (s, 1H); HPLC ES-MS m/z 522 ((M+H)⁺).

-   D5. General Method for the Deprotection of     N-(ω-Silyloxyalkyl)amides. Synthesis of     N-(4-Chloro-3-((trifluoromethyl)phenyl)-N′-(4-(4-(2-(N-(2-hydroxy)ethylcarbamoyl)pyridyloxyphenyl)     Urea.

To a solution of N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(4-(2-(N-(2-triisopropylsilyloxy) ethylcarbamoyl)pyridyloxyphenyl) urea (prepared in a manner analogous to Method C1a; 0.25 g, 0.37 mmol) in anh THF (2 mL) was tetrabutylammonium fluoride (1.0 M in THF; 2 mL). The mixture was stirred at room temperature for 5 min, then was treated with water (10 mL). The aqueous mixture was extracted with EtOAc (3×10 mL). The combined organic layers were dried (MgSO₄) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂; gradient from 100% hexane to 40% EtOAc/60% hexane) to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(4-(2-(N-(2-hydroxy)ethylcarbamoyl)pyridyloxyphenyl) urea as a white solid (0.019 g, 10%).

Listed below are compounds listed in the Tables below which have been synthesized according to the Detailed Experimental Procedures given above:

Syntheses of Exemplified Compounds (see Tables for compound characterization)

-   Entry 1: 4-(3-N-Methylcarbamoylphenoxy)aniline was prepared     according to Method A13. According to Method C3, 3-tert-butylaniline     was reacted with bis(trichloromethyl)carbonate followed by     4-(3-N-Methylcarbamoylphenoxy)aniline to afford the urea. -   Entry 2: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were     reacted according to Method A13, Step 1 to afford the     4-(4-acetylphenoxy)-1-nitrobenzene.     4-(4-Acetylphenoxy)-1-nitrobenzene was reduced according to Method     A13, Step 4 to afford 4-(4-acetylphenoxy)aniline. According to     Method C3, 3-tert-butylaniline was reacted with bis(trichloromethyl)     carbonate followed by 4-(4-acetylphenoxy)aniline to afford the urea. -   Entry 3: According to Method C2d, 3-tert-butylaniline was treated     with CDI, followed by     4-(3-N-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been     prepared according to Method A8, to afford the urea. -   Entry 4: 5-tert-Butyl-2-methoxyaniline was converted to     5-tert-butyl-2-methoxyphenyl isocyanate according to Method B1.     4-(3-N-Methylcarbamoylphenoxy)aniline, prepared according to Method     A13, was reacted with the isocyanate according to Method C1a to     afford the urea. -   Entry 5: According to Method C2d, 5-tert-butyl-2-methoxyaniline was     reacted with CDI followed by     4-(3-N-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been     prepared according to Method A8, to afford the urea. -   Entry 6: 5-(4-Aminophenoxy)isoindoline-1,3-dione was prepared     according to Method A3. According to Method 2d,     5-tert-butyl-2-methoxyaniline was reacted with CDI followed by     5-(4-aminophenoxy)isoindoline-1,3-dione to afford the urea. -   Entry 7: 4-(1-Oxoisoindolin-5-yloxy)aniline was synthesized     according to Method A12. According to Method 2d,     5-tert-butyl-2-methoxyaniline was reacted with CDI followed by     4-(1-oxoisoindolin-5-yloxy)aniline to afford the urea. -   Entry 8: 4-(3-N-Methylcarbamoylphenoxy)aniline was synthesized     according to Method A13. According to Method C2a,     2-methoxy-5-(trifluoromethyl)aniline was reacted with CDI followed     by 4-(3-N-methylcarbamoylphenoxy)aniline to afford the urea. -   Entry 9: 4-Hydroxyacetophenone was reacted with     2-chloro-5-nitropyridine to give 4-(4-acetylphenoxy)     -5-nitropyridine according to Method A3, Step 2. According to Method     A8, Step 4, 4-(4-acetylphenoxy)-5-nitropyridine was reduced to     4-(4-acetylphenoxy)-5-aminopyridine.     2-Methoxy-5-(trifluoromethyl)aniline was converted to     2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method     B1. The isocyanate was reacted with     4-(4-acetylphenoxy)-5-aminopyridine according to Method C1a to     afford the urea. -   Entry 10: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were     reacted according to Method A13, Step 1 to afford the     4-(4-acetylphenoxy)-1-nitrobenzene. 4-(4-Acetylphenoxy)     -1-nitrobenzene was reduced according to Method A13, Step 4 to     afford 4-(4-acetylphenoxy)aniline. According to Method C3,     5-(trifluoromethyl)-2-methoxybutylaniline was reacted with     bis(trichloromethyl) carbonate followed by     4-(4-acetylphenoxy)aniline to afford the urea. -   Entry 11: 4-Chloro-N-methyl-2-pyridinecarboxamide, which was     synthesized according to Method A2, Step 3a, was reacted with     3-aminophenol according to Method A2, Step 4 using DMAC in place of     DMF to give 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline.     According to Method C4, 2-methoxy-5-(trifluoromethyl)aniline was     reacted with phosgene followed by     3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea. -   Entry 12: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted     with ammonia according to Method A2, Step 3b to form     4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was     reacted with 3-aminophenol according to Method A2, Step 4 using DMAC     in place of DMF to give 3-(2-carbamoyl-4-pyridyloxy)aniline.     According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was     reacted with phosgene followed by     3-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea. -   Entry 13: 4-Chloro-N-methyl-2-pyridinecarboxamide was synthesized     according to Method A2, Step 3b.     4-Chloro-N-methyl-2-pyridinecarboxamide was reacted with     4-aminophenol according to Method A2, Step 4 using DMAC in place of     DMF to give 4-(2-(N-metbylcarbamoyl)-4-pyridyloxy)aniline. According     to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with     CDI followed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to     afford the urea. -   Entry 14: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted     with ammonia according to Method A2, Step 3b to form     4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was     reacted with 4-aminophenol according to Method A2, Step 4 using DMAC     in place of DMF to give 4-(2-carbamoyl-4-pyridyloxy)aniline.     According to Method C4, 2-methoxy-5-(trifluoromethyl)aniline was     reacted with phosgene followed by     4-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea. -   Entry 15: According to Method C2d,     5-(triflouromethyl)-2-methoxyaniline was reacted with CDI followed     by 4-(3-N-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been     prepared according to Method A8, to afford the urea. -   Entry 16: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline was     synthesized according to Method A5.     5-(Trifluoromethyl)-2-methoxyaniline was converted into     5-(trifluoromethyl) -2-methoxyphenyl isocyanate according to Method     B1. The isocyanate was reacted with     4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-methylaniline according to     Method C1c to afford the urea. -   Entry 17: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was     synthesized according to Method A6.     5-(Trifluoromethyl)-2-methoxyaniline was converted into     5-(trifluoromethyl) -2-methoxyphenyl isocyanate according to Method     B1. 5-(Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with     4-(2-(N-methylcarbamoyl) -4-pyridyloxy)-2-chloroaniline according to     Method C1a to afford the urea. -   Entry 18: According to Method A2, Step 4, 5-amino-2-methylphenol was     reacted with 4-chloro-N-methyl -2-pyridinecarboxamide, which had     been synthesized according to Method A2, Step 3b, to give     3-(2-(N-methylcarbamoyl)-4-pyridyloxy)4-methylaniline.     5-(Trifluoromethyl) -2-methoxyaniline was converted into     5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method     B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with     3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline according to     Method C1a to afford the urea. -   Entry 19: 4-Chloropyridine-2-carbonyl chloride was reacted with     ethylamine according to Method A2, Step 3b. The resulting     4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with     4-aminophenol according to Method A2, Step 4 to give     4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline.     5-(Trifluoromethyl)-2-methoxyaniline was converted into     5-(trifluoromethyl) -2-methoxyphenyl isocyanate according to Method     B1. 5-(Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with     4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline according to Method C1a     to afford the urea. -   Entry 20: According to Method A2, Step 4, 4-amino-2-chlorophenol was     reacted with 4-chloro-N-methyl -2-pyridinecarboxamide, which had     been synthesized according to Method A2, Step 3b, to give     4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline.     5-(Trifluoromethyl) -2-methoxyaniline was converted into     5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method     B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with     4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline according to     Method C1a to afford the urea. -   Entry 21: 4-(4-Methylthiophenoxy)-1-nitrobenzene was oxidized     according to Method A19, Step 1 to give     4-(4-methylsulfonylphenoxy)-1-nitrobenzene. The nitrobenzene was     reduced according to Method A19, Step 2 to give     4-(4-methylsulfonylphenoxy)-1-aniline. According to Method C1a,     5-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with     4-(4-methylsulfonylphenoxy) -1-aniline to afford the urea. -   Entry 22: 4-(3-carbamoylphenoxy)-1-nitrobenzene was reduced to     4-(3-carbamoylphenoxy)aniline according to Method A15, Step 4.     According to Method C1a, 5-(trifluoromethyl) -2-methoxyphenyl     isocyanate was reacted with 4-(3-carbamoylphenoxy)aniline to afford     the urea. -   Entry 23: 5-(4-Aminophenoxy)isoindoline-1,3-dione was synthesized     according to Method A3. 5-(Trifluoromethyl)-2-methoxyaniline was     converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate     according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl     isocyanate was reacted with 5-(4-aminophenoxy)isoindoline-1,3-dione     according to Method C1a to afford the urea. -   Entry 24: 4-Chloropyridine-2-carbonyl chloride was reacted with     dimethylamine according to Method A2, Step 3b. The resulting     4-chloro-N,N-dimethyl-2-pyridinecarboxamide was reacted with     4-aminophenol according to Method A2, Step 4 to give     4-(2-(N,N-dimethylcarbamoyl) -4-pyridyloxy)aniline.     5-(Trifluoromethyl)-2-methoxyaniline was converted into     5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method     B 1. 5-(Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted     with 4-(2-(N,N-dimethylcarbamoyl) -4-pyridyloxy)aniline according to     Method C1a to afford the urea. -   Entry 25: 4-(1-Oxoisoindolin-5-yloxy)aniline was synthesized     according to Method A12. 5-(Trifluoromethyl) -2-methoxyaniline was     treated with CDI, followed by 4-(1-oxoisoindolin-5-yloxy)aniline     according to Method C2d to afford the urea. -   Entry 26: 4-Hydroxyacetophenone was reacted with     4-fluoronitrobenzene according to Method A13, Step 1 to give     4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was reduced     according to Method A13, Step 4 to afford     4-(4-acetylphenoxy)aniline, which was converted to the     4-(4-(1-(N-methoxy)iminoethyl)phenoxyaniline HCl salt according to     Method A16. 5-(Trifluoromethyl)-2-methoxyaniline was converted into     5-(trifluoromethyl) -2-methoxyphenyl isocyanate according to Method     B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with     4-(4-(1-(N-methoxy)iminoethyl)phenoxyaniline HCl salt to Method C1a     to afford the urea. -   Entry 27: 4-Chloro-N-methylpyridinecarboxamide was synthesized as     described in Method A2, Step 3b. The chloropyridine was reacted with     4-aminothiophenol according to Method A2, Step 4 to give     4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. 5-(Trifluoromethyl)     -2-methoxyaniline was converted into     5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method     B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with     4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline according to Method     C1a to afford the urea. -   Entry 28: 5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione was     synthesized according to Method A9.     5-(Trifluoromethyl)-2-methoxyaniline was converted into     5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method     B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with     5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione according to Method     C1a to afford the urea. -   Entry 29: 4-Chloro-N-methylpyridinecarboxamide was synthesized as     described in Method A2, Step 3b. The chloropyridine was reacted with     3-aminothiophenol according to Method A2, Step 4 to give     3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. 5-(Trifluoromethyl)     -2-methoxyaniline was converted into     5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method     B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with     3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline according to Method     C1a to afford the urea. -   Entry 30: 4-Chloropyridine-2-carbonyl chloride was reacted with     isopropylamine according to Method A2, Step 3b. The resulting     4-chloro-N-isopropyl-2-pyridinecarboxamide was reacted with     4-aminophenol according to Method A2, Step 4 to give     4-(2-(N-isopropylcarbamoyl) -4-pyridyloxy)aniline.     5-(Trifluoromethyl)-2-methoxyaniline was converted into     5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method     B1. 5-(Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with     4-(2-(N-isopropylcarbamoyl) -4-pyridyloxy)aniline according to     Method C1a to afford the urea. -   Entry 31: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized     according to Method A14. 5-(Trifluoromethyl)-2-methoxyaniline was     converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate     according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl     isocyanate was reacted with     4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C1a     to afford the urea.     N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N′-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)     urea was saponified according to Method D4, Step 1, and the     corresponding acid was coupled with 4-(2-aminoethyl)morpholine to     afford the amide according to Method D4, Step 2. -   Entry 32: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized     according to Method A14. 5-(Trifluoromethyl)-2-methoxyaniline was     converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate     according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl     isocyanate was reacted with     4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C1a     to afford the urea.     N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N′-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)     urea was saponified according to Method D4, Step 1, and the     corresponding acid was coupled with methylamine according to Method     D4, Step 2 to afford the amide. -   Entry 33: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized     according to Method A14. 5-(Trifluoromethyl)-2-methoxyaniline was     converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate     according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl     isocyanate was reacted with     4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C1a     to afford the urea.     N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N′-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)     urea was saponified according to Method D4, Step 1, and the     corresponding acid was coupled with N,N-dimethylethylenediamine     according to Method D4, Step 2 to afford the amide. -   Entry 34: 4-(3-Carboxyphenoxy)aniline was synthesized according to     Method A11. 5-(Trifluoromethyl) -2-methoxyaniline was converted into     5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method     B1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)     -2-methoxyphenyl isocyanate according to Method C1f to afford     N-(5-(trifluoromethyl) -2-methoxyphenyl)-N′-(3-carboxyphenyl) urea,     which was coupled with 3-aminopyridine according to Method D1c. -   Entry 35: 4-(3-Carboxyphenoxy)aniline was synthesized according to     Method A11. 5-(Trifluoromethyl) -2-methoxyaniline was converted into     5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method     B1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)     -2-methoxyphenyl isocyanate according to Method C1f to afford     N-(5-(trifluoromethyl) -2-methoxyphenyl)-N′-(3-carboxyphenyl) urea,     which was coupled with N-(4-fluorophenyl)piperazine according to     Method D1c. -   Entry 36: 4-(3-Carboxyphenoxy)aniline was synthesized according to     Method A11. 5-(Trifluoromethyl) -2-methoxyaniline was converted into     5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method     B1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)     -2-methoxyphenyl isocyanate according to Method C1f to afford     N-(5-(trifluoromethyl) -2-methoxyphenyl)-N′-(3-carboxyphenyl) urea,     which was coupled with 4-fluoroaniline according to Method D1c. -   Entry 37: 4-(3-Carboxyphenoxy)aniline was synthesized according to     Method A11. 5-(Trifluoromethyl) -2-methoxyaniline was converted into     5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method     B1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)     -2-methoxyphenyl isocyanate according to Method C1f to afford     N-(5-(trifluoromethyl) -2-methoxyphenyl)-N′-(3-carboxyphenyl) urea,     which was coupled with 4-(dimethylamino)aniline according to Method     D1c. -   Entry 38: 4-(3-Carboxyphenoxy)aniline was synthesized according to     Method A11. 5-(Trifluoromethyl) -2-methoxyaniline was converted into     5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method     B1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)     -2-methoxyphenyl isocyanate according to Method C1f to afford     N-(5-(trifluoromethyl) -2-methoxyphenyl)-N′-(3-carboxyphenyl) urea,     which was coupled with 5-amino -2-methoxypyridine according to     Method D1c. -   Entry 39: 4-(3-Carboxyphenoxy)aniline was synthesized according to     Method A11. 5-(Trifluoromethyl) -2-methoxyaniline was converted into     5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method     B1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)     -2-methoxyphenyl isocyanate according to Method C1f to afford     N-(5-(trifluoromethyl) -2-methoxyphenyl)-N′-(3-carboxyphenyl) urea,     which was coupled with 4-morpholinoaniline according to Method D1c. -   Entry 40: 4-(3-Carboxyphenoxy)aniline was synthesized according to     Method A11. 5-(Trifluoromethyl) -2-methoxyaniline was converted into     5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method     B1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)     -2-methoxyphenyl isocyanate according to Method C1f to afford     N-(5-(trifluoromethyl) -2-methoxyphenyl)-N′-(3-carboxyphenyl) urea,     which was coupled with N-(2-pyridyl)piperazine according to Method     D1c. -   Entry 41: 4-(3-(N-Methylcarbamoyl)phenoxy)aniline was synthesized     according to Method A13. According to Method C3,     4-chloro-3-(trifluoromethyl)aniline was converted to the isocyanate,     then reacted with 4-(3-(N-Methylcarbamoyl)phenoxy)aniline to afford     the urea. -   Entry 42: 4-(2-N-Methylcarbamyl-4-pyridyloxy)aniline was synthesized     according to Method A2. 4-Chloro-3-(trifluoromethyl)phenyl     isocyanate was reacted with 4-(2-N-methylcarbamyl     -4-pyridyloxy)aniline according to Method C1a to afford the urea. -   Entry 43: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted     with ammonia according to Method A2, Step 3b to form     4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was     reacted with 4-aminophenol according to Method A2, Step 4 to form     4-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C1a,     4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with     4-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea. -   Entry 44: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted     with ammonia according to Method A2, Step 3b to form     4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was     reacted with 3-aminophenol according to Method A2, Step 4 to form     3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C1a,     4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with     3-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea. -   Entry 45: 4-Chloro-N-methyl-2-pyridinecarboxamide, which was     synthesized according to Method A2, Step 3a, was reacted with     3-aminophenol according to Method A2, Step 4 to form     3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method     C1a, 4-chloro -3-(trifluoromethyl)phenyl isocyanate was reacted with     3-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea. -   Entry 46: 5-(4-Aminophenoxy)isoindoline-1,3-dione was synthesized     according to Method A3. According to Method C1a,     4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with     5-(4-aminophenoxy)isoindoline-1,3-dione to afford the urea. -   Entry 47: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline was     synthesized according to Method A5. According to Method C1c,     4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with     5-(4-aminophenoxy)isoindoline-1,3-dione to afford the urea. -   Entry 48: 4-(3-N-Methylsulfamoyl)phenyloxy)aniline was synthesized     according to Method A15. According to Method C1a,     4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with     4-(3-N-methylsulfamoyl)phenyloxy)aniline to afford the urea. -   Entry 49: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was     synthesized according to Method A6. According to Method C1a,     4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with     4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline to afford the     urea. -   Entry 50: According to Method A2, Step 4, 5-amino-2-methylphenol was     reacted with 4-chloro-N-methyl -2-pyridinecarboxamide, which had     been synthesized according to Method A2, Step 3b, to give     3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. According to     Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was     reacted with 3-(2-(N-methylcarbamoyl) -4-pyridyloxy)-4-methylaniline     to afford the urea. -   Entry 51: 4-Chloropyridine-2-carbonyl chloride was reacted with     ethylamine according to Method A2, Step 3b. The resulting     4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with     4-aminophenol according to Method A2, Step 4 to give     4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline. According to Method     C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with     4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea. -   Entry 52: According to Method A2, Step 4, 4-amino-2-chlorophenol was     reacted with 4-chloro-N-methyl -2-pyridinecarboxamide, which had     been synthesized according to Method A2, Step 3b, to give     4-(2-(N-methylcarbamoyl)4-pyridyloxy)-3-chloroaniline. According to     Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was     reacted with 4-(2-(N-methylcarbamoyl) -4-pyridyloxy)-3-chloroaniline     to afford the urea. -   Entry 53: 4-(4-Methylthiophenoxy)-1-nitrobenzene was oxidized     according to Method A19, Step 1 to give     4-(4-methylsulfonylphenoxy)-1-nitrobenzene. The nitrobenzene was     reduced according to Method A19, Step 2 to give     4-(4-methylsulfonylphenoxy)-1-aniline. According to Method C1a,     4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with     4-(4-methylsulfonylphenoxy) -1-aniline to afford the urea. -   Entry 54: 4-Bromobenzenesulfonyl chloride was reacted with     methylamine according to Method A15, Step 1 to afford     N-methyl-4-bromobenzenesulfonamide.     N-Methyl-4-bromobenzenesulfonamide was coupled with phenol according     to Method A15, Step 2 to afford     4-(4-(N-methylsulfamoyl)phenoxy)benzene.     4-(4-(N-Methylsulfamoyl)phenoxy)benzene was converted into     4-(4-(N-methylsulfamoyl)phenoxy) -1-nitrobenzene according to Method     A15, Step 3. 4-(4-(N-Methylsulfamoyl)phenoxy)-1-nitrobenzene was     reduced to 4-(4-N-methylsulfamoyl)phenyloxy)aniline according to     Method A15, Step 4. According to Method C1a,     4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with     4-(3-N-methylsulfamoyl)phenyloxy)aniline to afford the urea. -   Entry 55: 5-Hydroxy-2-methylpyridine was coupled with     1-fluoro-4-nitrobenzene according to Method A18, Step 1 to give     4-(5-(2-Methyl)pyridyloxy)-1-nitrobenzene. The methylpyridine was     oxidized according to the carboxylic acid, then esterified according     to Method A18, Step 2 to give     4-(5-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene. The nitrobenzene     was reduced according the Method A18, Step 3 to give     4-(5-(2-methoxycarbonyl)pyridyloxy)aniline. The aniline was reacted     with 4-chloro-3-(trifluoromethyl)phenyl isocyanate according to     Method C1a to afford the urea. -   Entry 56: 5-Hydroxy-2-methylpyridine was coupled with     1-fluoro-4-nitrobenzene according to Method A18, Step 1 to give     4-(5-(2-Methyl)pyridyloxy)-1-nitrobenzene. The methylpyridine was     oxidized according to the carboxylic acid, then esterified according     to Method A18, Step 2 to give     4-(5-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene. The nitrobenzene     was reduced according the Method A18, Step 3 to give     4-(5-(2-methoxycarbonyl)pyridyloxy)aniline. The aniline was reacted     with 4-chloro-3-(trifluoromethyl)phenyl isocyanate according to     Method C1a to give     N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(methoxycarbonyl)-5-pyridyloxy)phenyl)     urea. The methyl ester was reacted with methylamine according to     Method D2 to afford     N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-5-pyridyloxy)phenyl)     urea. -   Entry 57: N-(4-Chloro-3-(trifluoromethyl)phenyl-N′-(4-aminophenyl)     urea was prepared according to Method C1d.     N-(4-Chloro-3-(trifluoromethyl)phenyl-N′-(4-aminophenyl) urea was     coupled with mono-methyl isophthalate according to Method D1a to     afford the urea. -   Entry 58: N-(4-Chloro-3-(trifluoromethyl)phenyl-N′-(4-aminophenyl)     urea was prepared according to Method C1d.     N-(4-Chloro-3-(trifluoromethyl)phenyl-N′-(4-aminophenyl) urea was     coupled with mono-methyl isophthalate according to Method D1a to     afford N-(4-chloro     -3-(trifluoromethyl)phenyl-N′-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl)     urea. According to Method D2,     N-(4-chloro-3-(trifluoromethyl)phenyl-N′-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl)     urea was reacted with methylamine to afford the corresponding methyl     amide. -   Entry 59: 4-Chloropyridine-2-carbonyl chloride was reacted with     dimethylamine according to Method A2, Step 3b. The resulting     4-chloro-N,N-dimethyl-2-pyridinecarboxamide was reacted with     4-aminophenol according to Method A2, Step 4 to give     4-(2-(N,N-dimethylcarbamoyl) -4-pyridyloxy)aniline. According to     Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was     reacted with 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline to     afford the urea. -   Entry 60: 4-Hydroxyacetophenone was reacted with     4-fluoronitrobenzene according to Method A13, Step 1 to give     4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was reduced     according to Method 13, Step 4 to afford 4-(4-acetylphenoxy)aniline,     which was converted to the 4-(4-(1-(N-methoxy)iminoethyl)     phenoxyaniline HCl salt according to Method A16. According to Method     C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with     4-(4-acetylphenoxy)aniline to afford the urea. -   Entry 61: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized     according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene     was coupled with 4-(2-aminoethyl)morpholine according to Method A13,     Step 3 to give 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)     -1-nitrobenzene. According to Method A13 Step 4,     4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)-1-nitrobenzene was     reduced to 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)aniline.     According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl     isocyanate was reacted with     4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)aniline to afford the     urea. -   Entry 62: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized     according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene     was coupled with 1-(2-aminoethyl)piperidine according to Method A13,     Step 3 to give     4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)-1-nitrobenzene.     According to Method A13 Step 4,     4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy) -1-nitrobenzene was     reduced to 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)aniline.     According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl     isocyanate was reacted with     4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)aniline to afford the     urea. -   Entry 63: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized     according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene     was coupled with tetrahydrofurfurylamine according to Method A13,     Step 3 to give 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)     -1-nitrobenzene. According to Method A13 Step 4,     4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene was     reduced to 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)aniline.     According to Method C1a, 4-chloro -3-(trifluoromethyl)phenyl     isocyanate was reacted with     4-(3-(N-(tetrahydrofurylmethyl)carbamoyl) phenoxy)aniline to afford     the urea. -   Entry 64: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized     according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene     was coupled with 2-aminomethyl-1-ethylpyrrolidine according to     Method A13, Step 3 to give     4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)     -1-nitrobenzene. According to Method A 13 Step 4,     4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzene     was reduced to     4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline.     According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl     isocyanate was reacted with     4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline to     afford the urea. -   Entry 65: 4-Chloro-N-methylpyridinecarboxamide was synthesized as     described in Method A2, Step 3b. The chloropyridine was reacted with     4-aminothiophenol according to Method A2, Step 4 to give     4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. According to Method     C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with     4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline to afford the urea. -   Entry 66: 4-Chloropyridine-2-carbonyl chloride was reacted with     isopropylamine according to Method A2, Step 3b. The resulting     4-chloro-N-isopropyl-2-pyridinecarboxamide was reacted with     4-aminophenol according to Method A2, Step 4 to give     4-(2-(N-isopropylcarbamoyl) -4-pyridyloxy)aniline. According to     Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was     reacted with 4-(2-(N-isopropylcarbamoyl)-4-pyridyloxy)aniline to     afford the urea. -   Entry 67:     N-(4-Chloro-3-(trifluoromethyl)phenyl-N′-(4-ethoxycarbonylphenyl)     urea was synthesized according to Method C1e.     N-(4-Chloro-3-(trifluoromethyl)phenyl-N′-(4-ethoxycarbonylphenyl)     urea was saponified according to Method D3 to give     N-(4-chloro-3-(trifluoromethyl)phenyl-N′-(4-carboxyphenyl) urea.     N-(4-Chloro-3-(trifluoromethyl)phenyl-N′-(4-carboxyphenyl) urea was     coupled with 3-methylcarbamoylaniline according to Method D1b to     give     N-(4-chloro-3-(trifluoromethyl)phenyl-N′-(4-(3-methylcarbamoylphenyl)carbamoylphenyl)     urea. -   Entry 68: 5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione was     synthesized according to Method A9. According to Method C1a,     4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with     5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione to afford the urea. -   Entry 69: 4-Chloro-N-methylpyridinecarboxamide was synthesized as     described in Method A2, Step 3b. The chloropyridine was reacted with     3-aminothiophenol according to Method A2, Step 4 to give     3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. According to Method     C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with     3 -(4-(2-(N-methylcarbamoyl)phenylthio)aniline to afford the urea. -   Entry 70:     4-(2-(N-(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was     synthesized according to Method A10. According to Method C1a,     4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with     4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline to     afford the urea. -   Entry 71: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized     according to Method A14.     4-Chloro-3-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted     with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method     C1a to afford the urea. N-(4-Chloro     -3-(trifluoromethyl)phenyl)-N′-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)     urea was saponified according to Method D4, Step 1, and the     corresponding acid was coupled with 4-(2-aminoethyl)morpholine to     afford the amide. -   Entry 72: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized     according to Method A14. 4-Chloro-3-(trifluoromethyl)phenyl     isocyanate was reacted with     4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C1a     to afford the urea. N-(5-(Trifluoromethyl)     -2-methoxyphenyl)-N′-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)     urea was saponified according to Method D4, Step 1, and the     corresponding acid was coupled with methylamine according to Method     D4, Step 2 to afford the amide. -   Entry 73: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized     according to Method A14. 4-Chloro-3-(trifluoromethyl)phenyl     isocyanate was reacted with     4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C1a     to afford the urea. N-(5-(Trifluoromethyl)     -2-methoxyphenyl)-N′-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)     urea was saponified according to Method D4, Step 1, and the     corresponding acid was coupled with N,N-dimethylethylenediamine     according to Method D4, Step 2 to afford the amide. -   Entry 74: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted     with 2-hydroxyethylamine according to Method A2, Step 3b to form     4-chloro-N-(2-triisopropylsilyloxy)ethylpyridine -2-carboxamide.     4-Chloro-N-(2-triisopropylsilyloxy)ethylpyridine -2-carboxamide was     reacted with triisopropylsilyl chloride, followed by 4-aminophenol     according to Method A17 to form     4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline.     According to Method C1a, 4-chloro -3-(trifluoromethyl)phenyl     isocyanate was reacted with     4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl) pyridyloxyaniline     to afford     N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(4-(2-(N-(2-triisopropylsilyloxy)     ethylcarbamoyl)pyridyloxyphenyl) urea. -   Entry 75: 4-(3-Carboxyphenoxy)aniline was synthesized according to     Method A11. 4-Chloro -3-(trifluoromethyl)phenyl isocyanate was     reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to     Method C1f to afford the urea, which was coupled with     3-aminopyridine according to Method D1c. -   Entry 76: 4-(3-Carboxyphenoxy)aniline was synthesized according to     Method A11. 4-Chloro -3-(trifluoromethyl)phenyl isocyanate was     reacted with 4-(3-carboxyphenoxy)aniline according to Method C1f to     afford the urea, which was coupled with N-(4-acetylphenyl)piperazine     according to Method D1c. -   Entry 77: 4-(3-Carboxyphenoxy)aniline was synthesized according to     Method A11. 4-Chloro -3-(trifluoromethyl)phenyl isocyanate was     reacted with 4-(3-carboxyphenoxy)aniline according to Method C1f to     afford the urea, which was coupled with 4-fluoroaniline according to     Method D1c. -   Entry 78: 4-(3-Carboxyphenoxy)aniline was synthesized according to     Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was     reacted with 4-(3-carboxyphenoxy)aniline according to Method C1f to     afford the urea, which was coupled with 4-(dimethylamino)aniline     according to Method D1c. -   Entry 79: 4-(3-Carboxyphenoxy)aniline was synthesized according to     Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was     reacted with 4-(3-carboxyphenoxy)aniline according to Method C1f to     afford the urea, which was coupled with N-phenylethylenediamine     according to Method D1c. -   Entry 80: 4-(3-Carboxyphenoxy)aniline was synthesized according to     Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was     reacted with 4-(3-carboxyphenoxy)aniline according to Method C1f to     afford the urea, which was coupled with 2-methoxyethylamine     according to Method D1c. -   Entry 81: 4-(3-Carboxyphenoxy)aniline was synthesized according to     Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was     reacted with 4-(3-carboxyphenoxy)aniline according to Method C1f to     afford the urea, which was coupled with 5-amino-2-methoxypyridine     according to Method D1c. -   Entry 82: 4-(3-Carboxyphenoxy)aniline was synthesized according to     Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was     reacted with 4-(3-carboxyphenoxy)aniline according to Method C1f to     afford the urea, which was coupled with 4-morpholinoaniline     according to Method D1c. -   Entry 83: 4-(3-Carboxyphenoxy)aniline was synthesized according to     Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was     reacted with 4-(3-carboxyphenoxy)aniline according to Method C1f to     afford the urea, which was coupled with N-(2-pyridyl)piperazine     according to Method D1c. -   Entry 84: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted     with 2-hydroxyethylamine according to Method A2, Step 3b to form     4-chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide.     4-Chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide was     reacted with triisopropylsilyl chloride, followed by 4-aminophenol     according to Method A17 to form     4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline.     According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl     isocyanate was reacted with     4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline     to give     N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyphenyl)     urea. The urea was deprotected according to Method D5 to afford     N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(4-(2-(N-(2-hydroxy)ethylcarbamoyl)pyridyloxyphenyl)     urea. -   Entry 85: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)aniline was     synthesized according to Method A2.     4-Bromo-3-(trifluoromethyl)aniline was converted to     4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.     According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl     isocyanate was reacted with     4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea. -   Entry 86: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was     synthesized according to Method A6.     4-Bromo-3-(trifluoromethyl)aniline was converted into     4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.     According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl     isocyanate was reacted with     4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline to afford the     urea. -   Entry 87: According to Method A2, Step 4, 4-amino-2-chlorophenol was     reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which had been     synthesized according to Method A2, Step 3b, to give     4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline.     4-Bromo-3-(trifluoromethyl)aniline was converted into     4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.     According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl     isocyanate was reacted with     4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the     urea. -   Entry 88: 4-Chloropyridine-2-carbonyl chloride was reacted with     ethylamine according to Method A2, Step 3b. The resulting     4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with     4-aminophenol according to Method A2, Step 4 to give     4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline.     4-Bromo-3-(trifluoromethyl)aniline was converted into     4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.     According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl     isocyanate was reacted with     4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea. -   Entry 89: 4-Chloro-N-methyl-2-pyridinecarboxamide, which was     synthesized according to Method A2, Step 3a, was reacted with     3-aminophenol according to Method A2, Step 4 to form     3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline.     4-Bromo-3-(trifluoromethyl)aniline was converted into     4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.     According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl     isocyanate was reacted with     3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea. -   Entry 90: According to Method A2, Step 4, 5-amino-2-methylphenol was     reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which had been     synthesized according to Method A2, Step 3b, to give     3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline.     4-Bromo-3-(trifluoromethyl)aniline was converted into     4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.     According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl     isocyanate was reacted with     3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline to afford the     urea. -   Entry 91: 4-Chloropyridine-2-carbonyl chloride was reacted with     dimethylamine according to Method A2, Step 3b. The resulting     4-chloro-N,N-dimethyl-2-pyridinecarboxamide was reacted with     4-aminophenol according to Method A2, Step 4 to give     4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline.     4-Bromo-3-(trifluoromethyl)aniline was converted into     4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.     According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl     isocyanate was reacted with     4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the     urea. -   Entry 92: 4-Chloro-N-methylpyridinecarboxamide was synthesized as     described in Method A2, Step 3b. The chloropyridine was reacted with     4-aminothiophenol according to Method A2, Step 4 to give     4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline.     4-Bromo-3-(trifluoromethyl)aniline was converted into     4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.     According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl     isocyanate was reacted with     4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline to afford the urea. -   Entry 93: 4-Chloro-N-methylpyridinecarboxamide was synthesized as     described in Method A2, Step 3b. The chloropyridine was reacted with     3-aminothiophenol according to Method A2, Step 4 to give     3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline.     4-Bromo-3-(trifluoromethyl)aniline was converted into     4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.     According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl     isocyanate was reacted with     3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline to afford the urea. -   Entry 94:     4-(2-(N-(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was     synthesized according to Method A10.     4-Bromo-3-(trifluoromethyl)aniline was converted into     4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.     According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl     isocyanate was reacted with     4-(2-(N-(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline to     afford the urea. -   Entry 95: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)aniline was     synthesized according to Method A2.     4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized     according to Method A7.     4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into     4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to     Method B1. According to Method C1a,     4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted     with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the     urea. -   Entry 96: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was     synthesized according to Method A6.     4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized     according to Method A7.     4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into     4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to     Method B1. According to Method C1a,     4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted     with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline afford     the urea. -   Entry 97: According to Method A2, Step 4, 4-amino-2-chlorophenol was     reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which had been     synthesized according to Method A2, Step 3b, to give     4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline.     4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized     according to Method A7.     4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into     4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to     Method B1. According to Method C1a,     4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted     with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to     afford the urea. -   Entry 98: 4-Chloro-N-methyl-2-pyridinecarboxamide, which was     synthesized according to Method A2, Step 3a, was reacted with     3-aminophenol according to Method A2, Step 4 to form     3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline.     4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized     according to Method A7.     4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into     4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to     Method B1. According to Method C1a,     4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate as was     reacted with 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to     afford the urea. -   Entry 99: 4-Chloropyridine-2-carbonyl chloride was reacted with     ethylamine according to Method A2, Step 3b. The resulting     4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with     4-aminophenol according to Method A2, Step 4 to give     4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline.     4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized     according to Method A7.     4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into     4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to     Method B1. According to Method C1a,     4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted     with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline to afford the     urea. -   Entry 100: 4-Chloropyridine-2-carbonyl chloride was reacted with     dimethylamine according to Method A2, Step 3b. The resulting     4-chloro-N,N-dimethyl-2-pyridinecarboxamide was reacted with     4-aminophenol according to Method A2, Step 4 to give     4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline.     4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized     according to Method A7.     4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into     4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to     Method B1. According to Method C1a,     4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted     with 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the     urea. -   Entry 101: 4-Chloro-N-methyl-2-pyridinecarboxamide, which was     synthesized according to Method A2, Step 3a, was reacted with     3-aminophenol according to Method A2, Step 4 to form     3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline.     2-Amino-3-methoxynaphthalene was synthesized as described Method A1.     According to Method C3, 2-amino-3-methoxynaphthalene was reacted     with bis(trichloromethyl) carbonate followed by     3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to form the urea. -   Entry 102: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)aniline was     synthesized according to Method A2.     5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline was synthesized     according to Method A4. 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline     was reacted with CDI followed by     4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline according to Method     C2d to afford the urea. -   Entry 103: 4-Chloro-N-methyl-2-pyridinecarboxamide was synthesized     according to Method A2, Step 3b.     4-Chloro-N-methyl-2-pyridinecarboxamide was reacted with     4-aminophenol according to Method A2, Step 4 using DMAC in place of     DMF to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. According     to Method C2b, reaction of 3-amino-2-methoxyquinoline with CDI     followed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline afforded     bis(4-(2-(N-methylcarbamoyl)-4-pyridlyoxy)phenyl)urea.

Listed in the Tables below are compounds which have been synthesized according to the Detailed Experimental Procedures given above:

Tables

The compounds listed in Tables 1-6 below were synthesized according to the general methods shown above, and the more detailed exemplary procedures are in the entry listings above and characterizations are indicated in the tables.

TABLE 1 3-tert-Butylphenyl Ureas

TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry R (° C.) (min.) R_(f) System [Source] Method 1

0.22 50%EtOAc/50%hexane 418(M + H) +(HPLCES-MS) A13 C3 2

0.58 50%EtOAc/50%hexane 403(M + H) +(HPLCES-MS) A13 C3 3

133-135 0.68 100%EtOAc 448(M + H) +(FAB) A8 C2d

TABLE 2 5-tert-Butyl-2-methoxyphenyl Ureas

TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry R (° C.) (min.) R_(f) System [Source] Method 4

5.93 448(M + H) +(HPLCES-MS) A13B1C1a 5

120-122 0.67 100%EtOAc 478(M + H) +(FAB) A8C2d 6

0.40 50%EtOAc/50%hexane 460(M + H) +(HPLCES-MS) A3C2d 7

0.79 50%EtOAc/50%hexane 446(M + H) +(HPLCES-MS) A12C2d

TABLE 3 5-(Trifluoromethyl)-2-methoxyphenyl Ureas

TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry R (° C.) (min.) R_(f) System [Source] Method 8

250 (dec) 460(M + H) +(FAB) A13 C2a 9

206-208 0.54 10%MeOH/90%CH2Cl2 446(M +H) +(HPLCES-MS) A3 step 2,A8 step 4,B1, C1a 10

0.33 50%EtOAc/50%petether 445(M + H) +(HPLCES-MS) A13 C3 11

0.20 2%Et3N/98%EtOAc 461(M + H) +(HPLCES-MS) A2 C4 12

0.27 1%Et3N/99%EtOAc 447(M + H) +(HPLCES-MS) A2 C4 13

0.62 100%EtOAc 461(M + H) +(FAB) A2 C2a 14

114-117 0.40 1%Et3N/99%EtOAc 447(M + H) +(FAB) A2 C4 15

232-235 0.54 100%EtOAc 490(M + H) +(FAB) A8 C2d 16

210-213 0.29 5%MeOH/45%EtOAc/50%petether 475(M + H) +(HPLCES-MS) A5B1 C1c 17

187-188 0.17 50%EtOAc/50%petether 495(M + H) +(HPLCES-MS) A6B1 C1a 18

0.48 100%EtOAc 475(M + H) +(HPLCES-MS) A2 step 4,B1 C1a 19

194-196 0.31 5%MeOH/45%EtOAc/50%petether 475(M + H) +(HPLCES-MS) A2B1 C1a 20

214-216 0.25 5%MeOH/45%EtOAc/50%petether 495(M + H) +(HPLCES-MS) A2 C1a 21

208-210 0.30 50%EtOAc/50%hexane 481(M + H) +(HPLCES-MS) A19 C2a 22

188-190 0.30 70%EtOAc/50%hexane 447(M + H) +(HPLCES-MS) A15,step 4,C1a 23

0.50 70%EtOAc/30%hexane 472(M + H) +(FAB) A3B1 C1a 24

203-205 0.13 100%EtOAc 479(M + H) +(HPLCES-MS) A2 B1C1a 25

0.09 75%EtOAc/25%hexane 458(M + H) +(HPLCES-MS) A12C2d 26

169-171 0.67 50%EtOAc/50%petether 474(M + H) +(HPLCES-MS) A13 step 1,A13 step 4,A16, B1C1a 27

218-219 0.40 50%EtOAc/50%petether 477(M + H) +(HPLCES-MS) A2 step 3b,A2 step 4,B1, C1a 28

212-214 0.30 40%EtOAc/60%hexane A9B1 C1a 29

0.33 50%EtOAc/50%petether 474(M + H) +(HPLCES-MS) A2 step 3b,A2 step 4,B1, C1a 30

210-211 A2 B1C1a 31

210-204 0.43 10%MeOH/CH2Cl2 A14 B1C1a D4 32

247-249 0.57 10%MeOH/CH2Cl2 A14 B1C1a D4 33

217-219 0.07 10%MeOH/CH2Cl2 A14 B1C1a D4 34

0.11 70%EtOAc/30%hexane A11 B1C1f D1c 35

0.38 70%EtOAc/30%hexane A11 B1C1f D1c 36

0.77 70%EtOAc/30%hexane A11 B1C1f D1c 37

0.58 70%EtOAc/30%hexane A11 B1C1f D1c 38

0.58 70%EtOAc/30%hexane A11 B1C1f D1c 39

0.17 70%EtOAc/30%hexane A11 B1C1f D1c 40

0.21 70%EtOAc/30%hexane A11 B1C1f D1c

TABLE 4 3-(Trifluoromethyl)-4-chlorophenyl Ureas

TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry R (° C.) (min.) R_(f) System [Source] Method 41

163-165 0.08 50%EtOAc/50%petether 464(M + H) +(HPLCES-MS) A13C3 42

215 0.06 50%EtOAc/50%petether 465(M + H) +(HPLCES-MS) A2C1a 43

0.10 50%EtOAc/50%petether 451(M + H) +(HPLCES-MS) A2C1a 44

0.25 30%EtOAc/70%petether 451(M + H) +(HPLCES-MS) A2C1a 45

0.31 30%EtOAc/70%petether 465(M + H) +(HPLCES-MS) A2C1a 46

176-179 0.23 40%EtOAc/60%hexane 476(M + H) +(FAB) A3C1a 47

0.29 5%MeOH/45%EtOAc/50%petether 478(M + H) +(HPLCES-MS) A5C1c 48

206-209 A15C1a 49

147-151 0.22 50%EtOAc/50%petether 499(M + H) +(HPLCES-MS) A6C1a 50

0.54 100%EtOAc 479(M + H) +(HPLCES-MS) A2C1a 51

187-189 0.33 5%MeOH/45%EtOAc/50%petether 479(M + H) +(HPLCES-MS) A2C1a 52

219 0.18 5%MeOH/45%EtOAc/50%petether 499(M + H) +(HPLCES-MS) A2C1a 53

246-248 0.30 50%EtOAc/50%hexane 485(M + H) +(HPLCES-MS) A19,C1a 54

196-200 0.30 70%EtOAc/30%hexane) 502(M + H) +(HPLCES-MS) A15C1a 55

228-230 0.30 30%EtOAc/70%CH2Cl2 466(M + H) +(HPLCES-MS) 56

238-245 57

221-222 0.75 80%EtOAc/20%hexane 492(M + H) +(FAB) C1dD1a 58

247 0.35 100%EtOAc C1dD1a D2 59

198-200 0.09 100%EtOAc 479(M + H) +(HPLCES-MS) A2C1a 60

158-160 0.64 50%EtOAc/50% petether 61

195-197 0.39 10%MeOH/CH2Cl2 A13C1a 62

170-172 0.52 10%MeOH/CH2Cl2 A13C1a 63

168-171 0.39 10%MeOH/CH2Cl2 A13C1a 64

176-177 0.35 10%MeOH/CH2Cl2 A13C1a 65

130-133 487(M + H) +(HPLCES-MS) A2B1C1a 66

155 A2C1a 67

225-229 0.23 100%EtOAc C1eD3D1b 68

234-236 0.29 40%EtOAc/60% hexane A9C1a 69

0.48 50%EtOAc/50% petether 481(M + H) +(HPLCES-MS) 70

0.46 5%MeOH/95%CH2Cl2 564(M + H) +(HPLCES-MS) A10C1a 71

199-201 0.50 10%MeOH/CH2Cl2 A14C1aD4 72

235-237 0.55 10%MeOH/CH2Cl2 A14C1aD4 73

200-201 0.21 50%MeOH/CH2Cl2 A14C1aD4 74

145-148 75

0.12 70%EtOAc/30%hexane 527(M + H) +(HPLCES-MS) A11C1fD1c 76

0.18 70%EtOAc/30%hexane A11C1fD1c 77

0.74 70%EtOAc/30%hexane A11C1fD1e 78

0.58 70%EtOAc/30%hexane A11C1fD1e 79

0.47 70%EtOAc/30%hexane 569(M + H) +(HPLCES-MS) A11C1fD1c 80

0.18 70%EtOAc/30%hexane 508(M + H) +(HPLCES-MS) A11C1fD1c 81

0.58 70%EtOAc/30%hexane 557(M + H) +(HPLCES-MS) A11C1fD1c 82

0.37 70%EtOAc/30%hexane 611(M + H) +(HPLCES-MS) A11C1fD1c 83

0.19 70%EtOAc/30%hexane A11C1fD1c 84

179-183 A2 A17C1a D5

TABLE 5 3-(Trifluoromethyl)-4-bromophenyl Ureas

TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry R (° C.) (min.) R_(f) System [Source] Method 85

186-187 0.13 50%EtOAc/50%pet ether 509(M + H) +(HPLC ES-MS) A2B1C1a 86

150-152 0.31 50%EtOAc/50%pet ether 545(M + H) +(HPLC ES-MS) A6B1C1a 87

217-219 0.16 50%EtOAc/50%pet ether 545(M + H) +(HPLC ES-MS) A2B1C1a 88

183-184 0.31 50%EtOAc/50%pet ether 525(M + H) +(HPLC ES-MS) A2B1C1a 89

0.21 50%EtOAc/50%pet ether 511(M + H) +(HPLC ES-MS) A2B1C1a 90

0.28 50%EtOAc/50%pet ether 525(M + H) +(HPLC ES-MS) A2B1C1a 91

214-216 0.28 50%EtOAc/50%pet ether 522(M + H) +(HPLC ES-MS) A2B1C1a 92

0.47 50%EtOAc/50%pet ether 527(M + H) +(HPLC ES-MS) A2 step 3b,A2 step 4,B1, C1a 93

0.46 50%EtOAc/50%pet ether 527(M + H) +(HPLC ES-MS) A2 step 3b,A2 step 4,B1, C1a 94

145-150 0.41 5%MeOH/95%CH2Cl2 A10B1C1a

TABLE 6 5-(Trifluoromethyl)-4-chloro-2-methoxyphenyl Ureas

TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry R (° C.) (min.) R_(f) System [Source] Method 95

140-144 0.29 5%MeOH/45%EtOAc/50%pet ether 495(M + H) +(HPLCES-MS) A2A7B1C1a 96

244-245 0.39 5%MeOH/45%EtOAc/50%pet ether 529(M + H) +(HPLCES-MS) A6A7B1C1a 97

220-221 0.25 5%MeOH/45%EtOAc/50%pet ether 529(M + H) +(HPLCES-MS) A2A7B1C1a 98

0.27 5%MeOH/45%EtOAc/50%pet ether 495(M + H) +(HPLCES-MS) A2A7B1C1a 99

180–181 0.52 5%MeOH/45%EtOAc/50%pet ether 509(M + H) +(HPLCES-MS) A2A7B1C1a 100

162-165 A2A7B1C1a

TABLE 7 Additional Ureas TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry R (° C.) (min.) R_(f) System [Source] Method 101

162-165 A1A2C3 102

0.10 50%EtOAc/50%hexane 442(M + H) +(HPLCES-MS) A2A4C2d 103

125-130 0.24 40%EtOAc/60%hexane 512(M + H) +(FAB) A2C2b

BIOLOGICAL EXAMPLES

P38 Kinase Assay:

The in vitro inhibitory properties of compounds were determined using a p38 kinase inhibition assay. P38 activity was detected using an in vitro kinase assay run in 96-well microtiter plates. Recombinant human p38 (0.5 μg/mL) was mixed with substrate (myelin basic protein, 5 μg/mL) in kinase buffer (25 mM Hepes, 20 mM MgCl₂ and 150 mM NaCl) and compound. One μCi/well of ³³P-labeled ATP (10 μM) was added to a final volume of 100 μL. The reaction was run at 32° C. for 30 min. and stopped with a 1M HCl solution. The amount of radioactivity incorporated into the substrate was determined by trapping the labeled substrate onto negatively charged glass fiber filter paper using a 1% phosphoric acid solution and read with a scintillation counter. Negative controls include substrate plus ATP alone.

All compounds exemplified displayed p38 IC₅₀s of between 1 nM and 10 μM.

LPS Induced TNFα Production in Mice:

The in vivo inhibitory properties of selected compounds were determined using a murine LPS induced TNFα production in vivo model. BALB/c mice (Charles River Breeding Laboratories; Kingston, N.Y.) in groups of ten were treated with either vehicle or compound by the route noted. After one hour, endotoxin (E. coli lipopolysaccharide (LPS) 100 μg) was administered intraperitoneally (i.p.). After 90 min, animals were euthanized by carbon dioxide asphyxiation and plasma was obtained from individual animals by cardiac puncture ionto heparinized tubes. The samples were clarified by centrifugation at 12,500×g for 5 min at 4° C. The supernatants were decanted to new tubes, which were stored as needed at −20° C. TNFα levels in sera were measured using a commercial murine TNF ELISA kit (Genzyme).

The preceeding examples can be repeated with similar success by substituting the generically of specifically described reactants and/or operating conditions of this invention for those used in the preceeding examples

From the foregoing discussion, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

In Vitro raf Kinase Assay:

In an in vitro kinase assay, raf is incubated with MEK in 20 mM Tris-HCl, pH 8.2 containing 2 mM 2-mercaptoethanol and 100 mM NaCl. This protein solution (20 μL) is mixed with water (5 μL) or with compounds diluted with distilled water from 10 mM stock solutions of compounds dissolved in DMSO. The kinase reaction is initiated by adding 25 μL [γ-³³P]ATP (1000-3000 dpm/pmol) in 80 mM Tris-HCl, pH 7.5, 120 mM NaCl, 1.6 mM DTT, 16 mM MgCl₂. The reaction mixtures are incubated at 32° C., usually for 22 min. Incorporation of ³³P into protein is assayed by harvesting the reaction onto phosphocellulose mats, washing away free counts with a 1% phosphoric acid solution and quantitating phosphorylation by liquid scintillation counting. For high throughput screening, 10 μM ATP and 0.4 μM MEK are used. In some experiments, the kinase reaction is stopped by adding an equal amount of Laemmli sample buffer. Samples are boiled 3 min and the proteins resolved by electrophoresis on 7.5% Laemmli gels. Gels are fixed, dried and exposed to an imaging plate (Fuji). Phosphorylation is analyzed using a Fujix Bio-Imaging Analyzer System.

All compounds exemplified displayed IC₅₀s of between 1 nM and 10 μM.

Cellular Assay:

For in vitro growth assay, human tumor cell lines, including but not limited to HCT116 and DLD-1, containing mutated K-ras genes are used in standard proliferation assays for anchorage dependent growth on plastic or anchorage independent growth in soft agar. Human tumor cell lines were obtained from ATCC (Rockville Md.) and maintained in RPMI with 10% heat inactivated fetal bovine serum and 200 mM glutamine. Cell culture media and additives are obtained from Gibco/BRL (Gaithersburg, Md.) except for fetal bovine serum (JRH Biosciences, Lenexa, Kans.). In a standard proliferation assay for anchorage dependent growth, 3×10³ cells are seeded into 96-well tissue culture plates and allowed to attach overnight at 37° C. in a 5% CO₂ incubator. Compounds are titrated in media in dilution series and added to 96 well cell cultures. Cells are allowed to grow 5 days typically with a feeding of fresh compound containing media on day three. Proliferation is monitored by measuring metabolic activity with standard XTT calorimetric assay (Boehringer Mannheim) measured by standard ELISA plate reader at OD 490/560, or by measuring ³H-thymidine incorporation into DNA following an 8 h culture with 1 μCu ³H-thymidine, harvesting the cells onto glass fiber mats using a cell harvester and measuring ³H-thymidine incorporation by liquid scintillant counting.

For anchorage independent cell growth, cells are plated at 1×10³ to 3×10³ in 0.4% Seaplaque agarose in RPMI complete media, overlaying a bottom layer containing only 0.64% agar in RPMI complete media in 24-well tissue culture plates. Complete media plus dilution series of compounds are added to wells and incubated at 37° C. in a 5% CO₂ incubator for 10-14 days with repeated feedings of fresh media containing compound at 3-4 day intervals. Colony formation is monitored and total cell mass, average colony size and number of colonies are quantitated using image capture technology and image analysis software (Image Pro Plus, media Cybernetics).

These assays establish that the compounds of Formula I are active to inhibit raf kinase activity and to inhibit oncogenic cell growth.

In Vivo Assay:

An in vivo assay of the inhibitory effect of the compounds on tumors (e.g., solid cancers) mediated by raf kinase can be performed as follows:

CDI nu/nu mice (6-8 weeks old) are injected subcutaneously into the flank at 1×10⁶ cells with human colon adenocarcinoma cell line. The mice are dosed i.p., i.v. or p.o. at 10, 30, 100, or 300 mg/Kg beginning on approximately day 10, when tumor size is between 50-100 mg. Animals are dosed for 14 consecutive days; tumor size is monitored with calipers twice a week.

The inhibitory effect of the compounds on raf kinase and therefore on tumors (e.g., solid cancers) mediated by raf kinase can further be demonstrated in vivo according to the technique of Monia et al. (Nat. Med. 1996, 2, 668-75).

The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. 

1. A compound of formula (Ia)

wherein, Y is NHR, Hal is chlorine or bromine, R is H, CH₃ or CH₂OH, and X¹ to X⁷ are each, independently, H, OH or —OC(O)C₁-C₄ alkyl, or a salt or purified stereoisomer thereof, with the proviso that at least one of X¹ to X⁷ is OH or —OC(O)C₁-C₄ alkyl.
 2. A compound of claim 1 wherein X¹ is OH or —OC(O)C₁-C₄ alkyl.
 3. A compound of claim 1 wherein X² is OH or —OC(O)C₁-C₄ alkyl.
 4. A compound of claim 1 wherein X³ is OH or —OC(O)C₁-C₄ alkyl.
 5. A compound of claim 1 wherein X⁴ is OH or —OC(O)C₁-C₄ alkyl.
 6. A compound of claim 1 wherein X⁵ is OH or —OC(O)C₁-C₄ alkyl.
 7. A compound of claim 1 wherein X⁶ is OH or —OC(O)C₁-C₄ alkyl.
 8. A compound of claim 1 wherein X⁷ is OH or —OC(O)C₁-C₄ alkyl.
 9. A compound of claim 1 wherein Hal is chlorine.
 10. A compound of claim 1 which is 4-{4-[({[4-chloro-3-(trifluoromethyl) phenyl]amino}carbonyl)amino]2-(hydroxy)phenoxy}-2-pyridine carboxamide.
 11. A compound of claim 1 which is 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]3-(hydroxy)phenoxy}-2-pyridine carboxamide.
 12. A compound of claim 1 which is 4-{4-[({[4-chloro-3-(trifluoromethyl) phenyl]amino}carbonyl)amino]5-(hydroxy)phenoxy}-2-pyridine carboxamide.
 13. A compound of claim 1 which is 4-{4-[({[4-chloro-3-(trifluoromethyl) phenyl]amino}carbonyl)amino]6-(hydroxy)phenoxy}-2-pyridine carboxamide.
 14. A compound of formula (Ib)

wherein, Y is NHR, Hal is chlorine or bromine, R is H, CH₃ or CH₂OH, and X⁴ to X⁷ are each, independently, H, OH or —OC(O)C₁-C₄ alkyl, or a salt or purified stereoisomer thereof, with the proviso that at least one of X⁴ to X⁷ is OH or —OC(O)C₁-C₄ alkyl.
 15. A compound of formula (Ic)

wherein, Hal is chlorine or bromine, and X¹ to X⁷ are each, independently, H, OH or —OC(O)C₁-C₄ alkyl, or a salt or purified stereoisomer thereof, with the proviso that at least one of X¹ to X⁷ is OH or —OC(O)C₁-C₄ alkyl. 